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KEY POINTS * Pain is the primary reason why people seek medical care; more than 40% of the US population is affected by chronic pain. * Opioids, which are the most commonly used and often

the most effective class of analgesics, produce tolerance, dependence and constipation, and are associated with major abuse liabilities. The respiratory depression associated with high doses

has led to a catastrophic increase in the number of drug overdose deaths in the United States. * Several new or previously overlooked targets are gaining significant attention. In the field

of G-protein-coupled receptors (GPCRs), these include new ligands targeting opioid receptor heteromers, different opioid receptor subtypes and biased agonists. Non-opioid GPCRs currently

being pursued include cannabinoid receptor 2 (CB2), angiotensin type 2 receptor (AT2R) and chemokine receptors. * Various academic and industry groups are pursuing ion channel strategies by

targeting sodium, potassium and calcium channels — specifically, certain Nav1.7, Nav1.8 and voltage-dependent calcium channel (Cavs) ligands are showing particular promise in early

preclinical and clinical trials. * Several enzyme targets that modulate pain pathways are also being pursued. * Despite considerable efforts, there have been several high-profile failures of

novel analgesics in the clinic. * Barriers that need to be overcome to develop efficacious analgesics include issues related to the lack of predictability of preclinical models in certain

contexts, the translation of pathways from animal models to humans, exaggerated placebo effects and issues with clinical trial design. ABSTRACT Acute and chronic pain complaints, although

common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse

effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying

pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer

opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors. Access through your

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VALIDATION OF BIOMARKERS TO AID THE DEVELOPMENT OF SAFE AND EFFECTIVE PAIN THERAPEUTICS: CHALLENGES AND OPPORTUNITIES Article 15 June 2020 PATHOLOGY OF PAIN AND ITS IMPLICATIONS FOR

THERAPEUTIC INTERVENTIONS Article Open access 08 June 2024 DEZOCINE AS A POTENT ANALGESIC: OVERVIEW OF ITS PHARMACOLOGICAL CHARACTERIZATION Article 04 November 2021 CHANGE HISTORY * _ 23

JUNE 2017 In the original published article, the ligands RB-64 and PZM21 have been shown as attributed to Trevena in table 1 in the 'biased GPCR ligands' row. This error has been

corrected in the HTML and PDF versions of the article. _ * _ 06 OCTOBER 2017 The compounds APD371,LY2828360, S-777469 and KHK6188 were incorrectly referred to as inhibitors of the

cannabinoid receptors CB1 and CB2 in Table 1, when they are cannabinoid receptor agonists. In addition, KHK6188 is not currently in a Phase 2 clinical trial for neuropathic pain as stated in

Table 1 and development of this agent has been discontinued. The error has been corrected in the html and pdf versions online. _ REFERENCES * Dubois, M. Y., Gallagher, R. M. & Lippe, P.

M. Pain medicine position paper. _Pain Med._ 10, 972–1000 (2009). PubMed  Google Scholar  * Johannes, C. B., Le, T. K., Zhou, X., Johnston, J. A. & Dworkin, R. H. The prevalence of

chronic pain in United States adults: results of an Internet-based survey. _J. Pain_ 11, 1230–1239 (2010). PubMed  Google Scholar  * Volkow, N. D. & McLellan, A. T. Opioid abuse in

chronic pain — misconceptions and mitigation strategies. _N. Engl. J. Med._ 374, 1253–1263 (2016). THIS REVIEW HIGHLIGHTS COMMON MISCONCEPTIONS ABOUT ABUSE-RELATED LIABILITIES OF

PRESCRIPTION OPIOIDS AND PROPOSES STRATEGIES THAT COULD HELP TO MITIGATE THESE RISKS. CAS  PubMed  Google Scholar  * Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of

persistent peripheral neuropathic pain. _Pain_ 87, 149–158 (2000). IN THIS STUDY, THE AUTHORS DESCRIBE A TECHNIQUE FOR MODELLING PERIPHERAL NEUROPATHIC PAIN IN LABORATORY RODENTS. CAS 

PubMed  Google Scholar  * Honore, P. et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory

neurons. _Neuroscience_ 98, 585–598 (2000). CAS  PubMed  Google Scholar  * Costigan, M. et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.

_Brain_ 133, 2519–2527 (2010). THIS RESEARCH ARTICLE DESCRIBES A PUTATIVE HUMAN PAIN GENE THAT COULD INFORM THE SELECTION OF NOVEL DRUG TARGETS FOR PATIENTS WITH NEUROPATHIC PAIN. IT MAY

HELP TO EXPLAIN WHY SOME, BUT NOT ALL, PEOPLE WITH NERVE INJURY PROGRESS TO CHRONIC PAIN. PubMed  PubMed Central  Google Scholar  * von Hehn, C. A., Baron, R. & Woolf, C. J.

Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. _Neuron_ 73, 638–652 (2012). THIS WORK DESCRIBES HOW THE VARIABLE EXPRESSION OF SENSORY NERVE INJURY SYMPTOMS CAN

PROVIDE INSIGHTS INTO THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS AND GUIDANCE FOR THE DEVELOPMENT OF PERSONALIZED PAIN THERAPIES. CAS  PubMed  PubMed Central  Google Scholar  * Ji, R. R.,

Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. _Nat. Rev. Drug Discov._ 13, 533–548 (2014). HERE, THE AUTHORS DISCUSS EMERGING NEUROINFLAMMATORY PAIN

TARGETS AND DESCRIBE POTENTIAL THERAPEUTIC OPPORTUNITIES TO TARGET EXCESSIVE NEUROINFLAMMATION. CAS  PubMed  PubMed Central  Google Scholar  * Latremoliere, A. & Woolf, C. J. Central

sensitization: a generator of pain hypersensitivity by central neural plasticity. _J. Pain_ 10, 895–926 (2009). THIS WORK DESCRIBES THE MECHANISMS AND TRIGGERS THAT UNDERLIE THE INITIATION

AND MAINTENANCE OF CENTRAL SENSITIZATION, AND HOW THEY ARE ALTERED BY CHANGES IN THE PROPERTIES AND EXPRESSION PATTERNS OF GLUTAMATE RECEPTORS. PubMed  PubMed Central  Google Scholar  *

Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. _Cell_ 139, 267–284 (2009). IN THIS PIECE, THE AUTHORS REVIEW THE BIOLOGICAL

UNDERPINNINGS OF SOMATOSENSATION AT THE CIRCUIT, CELLULAR AND SUBCELLULAR LEVELS, WITH PARTICULAR EMPHASIS ON PAIN-RELATED RECEPTORS AND MECHANISMS. CAS  PubMed  PubMed Central  Google

Scholar  * Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. _J. Clin. Invest._ 120, 3779–3787 (2010). THIS REVIEW EXPLORES EVIDENCE THAT CENTRAL MODULATORY

CIRCUITS CAN DRAMATICALLY CHANGE THE SUBJECTIVE EXPERIENCE OF PAINFUL STIMULI. CAS  PubMed  PubMed Central  Google Scholar  * Vardeh, D., Mannion, R. J. & Woolf, C. J. Toward a

mechanism-based approach to pain diagnosis. _J. Pain_ 17, T50–T69 (2016). HERE, THE AUTHORS PROPOSE THAT IDENTIFYING SPECIFIC MECHANISMS THAT UNDERLIE CHRONIC PAIN COULD PROVIDE THE BASIS

FOR A PERSONALIZED-MEDICINE APPROACH TO ANALGESIA. PubMed  PubMed Central  Google Scholar  * Woolf, C. J. Overcoming obstacles to developing new analgesics. _Nat. Med._ 16, 1241–1247 (2010).

THIS ARTICLE DISCUSSES THE MANY COMPLEXITIES THAT HAVE MADE THE DEVELOPMENT OF NEW ANALGESICS SO CHALLENGING. CAS  PubMed  Google Scholar  * Andrews, N. A. et al. Ensuring transparency and

minimization of methodologic bias in preclinical pain research: PPRECISE considerations. _Pain_ 157, 901–909 (2016). HERE, MEMBERS OF THE PRECLINICAL PAIN RESEARCH CONSORTIUM FOR

INVESTIGATING SAFETY AND EFFICACY (PPRECISE) WORKING GROUP PROPOSE NEW VOLUNTARY STANDARDS OF SCIENTIFIC RIGOUR AND TRANSPARENT REPORTING TO PROMOTE MORE-EFFICIENT ADVANCEMENT OF THE SEARCH

FOR NEW PAIN TREATMENTS. PubMed  Google Scholar  * Singla, N. et al. Assay sensitivity of pain intensity versus pain relief in acute pain clinical trials: ACTTION systematic review and

meta-analysis. _J. Pain_ 16, 683–691 (2015). THIS META-ANALYSIS FOUND THAT FOR PRECLINICAL ACUTE PAIN TRIALS, READOUTS OF TOTAL PAIN RELIEF MAY BE MORE SENSITIVE TO TREATMENT THAN SUMMED

PAIN INTENSITY DIFFERENCES. PubMed  Google Scholar  * Finnerup, N. B. et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. _Lancet Neurol._ 14,

162–173 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. _Annu.

Rev. Neurosci._ 32, 1–32 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Patapoutian, A., Tate, S. & Woolf, C. J. Transient receptor potential channels: targeting pain at the

source. _Nat. Rev. Drug Discov._ 8, 55–68 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Woolf, C. J. Pain: morphine, metabolites, mambas, and mutations. _Lancet Neurol._ 12, 18–20

(2013). PubMed  Google Scholar  * Woolf, C. J. & Salter, M. W. Neuronal plasticity: increasing the gain in pain. _Science_ 288, 1765–1769 (2000). IN THIS REVIEW, THE AUTHORS

CONCEPTUALIZE HOW PLASTICITY IN ASCENDING SENSORY PATHWAYS MAY ELICIT PAIN HYPERSENSITIVITY BY INCREASING SIGNAL GAIN. CAS  PubMed  Google Scholar  * Chiu, I. M., von Hehn, C. A. &

Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. _Nat. Neurosci._ 15, 1063–1067 (2012). CAS  PubMed  PubMed Central  Google Scholar

  * Woolf, C. J. What is this thing called pain? _J. Clin. Invest._ 120, 3742–3744 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Julius, D. & Basbaum, A. I. Molecular mechanisms

of nociception. _Nature_ 413, 203–210 (2001). HERE, THE AUTHORS DESCRIBE MOLECULAR MECHANISMS OF PRIMARY AFFERENT NEURONS, THEIR MODALITY SENSITIVITIES AND VARIOUS TRANSDUCERS, PEPTIDES,

LIPIDS AND GROWTH FACTORS THAT SIGNAL PAIN AND MEDIATE PAIN-RELATED SIGNALS. CAS  PubMed  Google Scholar  * Michaud, K., Bombardier, C. & Emery, P. Quality of life in patients with

rheumatoid arthritis: does abatacept make a difference? _Clin. Exp. Rheumatol._ 25, S35–S45 (2007). CAS  PubMed  Google Scholar  * Drenth, J. P. & Waxman, S. G. Mutations in

sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. _J. Clin. Invest._ 117, 3603–3609 (2007). CAS  PubMed  PubMed Central  Google Scholar  * Woolf, C. J. Central

sensitization: implications for the diagnosis and treatment of pain. _Pain_ 152, S2–S15 (2011). PubMed  Google Scholar  * Hains, B. C. et al. Upregulation of sodium channel Nav1.3 and

functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. _J. Neurosci._ 23, 8881–8892 (2003). CAS  PubMed  PubMed Central 

Google Scholar  * Nassar, M. A. et al. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. _Mol. Pain_ 2, 33 (2006). PubMed  PubMed Central  Google

Scholar  * Dong, X. W. et al. Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.

_Neuroscience_ 146, 812–821 (2007). CAS  PubMed  Google Scholar  * Jarvis, M. F. et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and

inflammatory pain in the rat. _Proc. Natl Acad. Sci. USA_ 104, 8520–8525 (2007). CAS  PubMed  Google Scholar  * Ekberg, J. et al. muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron

specific sodium channels and chronic pain behavior without motor deficits. _Proc. Natl Acad. Sci. USA_ 103, 17030–17035 (2006). CAS  PubMed  Google Scholar  * Gold, M. S. et al.

Redistribution of NaV1.8 in uninjured axons enables neuropathic pain. _J. Neurosci._ 23, 158–166 (2003). CAS  PubMed  PubMed Central  Google Scholar  * Joshi, S. K. et al. Involvement of the

TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states. _Pain_ 123, 75–82 (2006). CAS  PubMed  Google Scholar  * Roza, C., Laird, J. M.,

Souslova, V., Wood, J. N. & Cervero, F. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. _J.

Physiol._ 550, 921–926 (2003). CAS  PubMed  PubMed Central  Google Scholar  * Fritch, P. C. et al. Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain. _J.

Med. Chem._ 53, 887–896 (2010). CAS  PubMed  Google Scholar  * Dost, R., Rostock, A. & Rundfeldt, C. The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel

activation. _Naunyn Schmiedebergs Arch. Pharmacol._ 369, 382–390 (2004). CAS  PubMed  Google Scholar  * Lee, S. Pharmacological inhibition of voltage-gated Ca2+ channels for chronic pain

relief. _Curr. Neuropharmacol._ 11, 606–620 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Stemkowski, P. L., Noh, M. C., Chen, Y. & Smith, P. A. Increased excitability of

medium-sized dorsal root ganglion neurons by prolonged interleukin-1β exposure is K+ channel dependent and reversible. _J. Physiol._ 593, 3739–3755 (2015). CAS  PubMed  PubMed Central 

Google Scholar  * Zogopoulos, P., Vasileiou, I., Patsouris, E. & Theocharis, S. E. The role of endocannabinoids in pain modulation. _Fundam. Clin. Pharmacol._ 27, 64–80 (2013). CAS 

PubMed  Google Scholar  * Gutenstein, H. & Akil, H. in _Goodman and Gilman's Pharmacological Basis of Therapeutics_ Ch. 21 (eds Brunton, L., Lazo, J. & Parker, K.) 547–590 (The

McGraw Hill companies, 2006). CHAPTER 21 OF THIS AUTHORITATIVE PHARMACOLOGY TEXT PROVIDES A THOROUGH OVERVIEW OF OPIOID ANALGESIC PHARMACOLOGY. Google Scholar  * Fries, D. S. in _Principles

of Medicinal Chemistry_ Ch. 14 (eds Foye, W. O., Lemke, T. L. & Williams,D. A.) 247–269 (William & Wilkins, 1995). CHAPTER 14 OF THIS ESSENTIAL MEDICINAL CHEMISTRY SOURCE DESCRIBES

THE MEDICINAL CHEMISTRY OF COMMON OPIOID AND ANTI-INFLAMMATORY ANALGESICS. Google Scholar  * Lesniak, A. & Lipkowski, A. W. Opioid peptides in peripheral pain control. _Acta Neurobiol.

Exp. (Wars.)_ 71, 129–138 (2011). Google Scholar  * Navratilova, E. et al. Positive emotions and brain reward circuits in chronic pain. _J. Comp. Neurol._ 524, 1646–1652 (2016). PubMed 

PubMed Central  Google Scholar  * Navratilova, E. & Porreca, F. Reward and motivation in pain and pain relief. _Nat. Neurosci._ 17, 1304–1312 (2014). CAS  PubMed  PubMed Central  Google

Scholar  * Kolodny, A. et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. _Annu. Rev. Public Health_ 36, 559–574 (2015). PubMed  Google

Scholar  * Cassidy, T. A., DasMahapatra, P., Black, R. A., Wieman, M. S. & Butler, S. F. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent

opioid formulation. _Pain Med._ 15, 440–451 (2014). PubMed  Google Scholar  * Kunins, H. V. Abuse-deterrent opioid formulations: part of a public health strategy to reverse the opioid

epidemic. _JAMA Intern. Med._ 175, 987–988 (2015). PubMed  Google Scholar  * Chilcoat, H. D., Coplan, P. M., Harikrishnan, V. & Alexander, L. Decreased diversion by doctor-shopping for a

reformulated extended release oxycodone product (OxyContin). _Drug Alcohol Depend._ 165, 221–228 (2016). PubMed  Google Scholar  * Coplan, P. M. et al. The effect of an abuse-deterrent

opioid formulation on opioid abuse-related outcomes in the post-marketing setting. _Clin. Pharmacol. Ther._ 100, 275–286 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Cicero, T. J.,

Ellis, M. S. & Surratt, H. L. Effect of abuse-deterrent formulation of OxyContin. _N. Engl. J. Med._ 367, 187–189 (2012). CAS  PubMed  Google Scholar  * Cicero, T. J., Ellis, M. S.

& Kasper, Z. A. A tale of 2 ADFs: differences in the effectiveness of abuse-deterrent formulations of oxymorphone and oxycodone extended-release drugs. _Pain_ 157, 1232–1238 (2016). CAS

  PubMed  Google Scholar  * Walsh, S. L., Strain, E. C., Abreu, M. E. & Bigelow, G. E. Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in

humans. _Psychopharmacology (Berl.)_ 157, 151–162 (2001). CAS  Google Scholar  * Pallasch, T. J. & Gill, C. J. Butorphanol and nalbuphine: a pharmacologic comparison. _Oral Surg. Oral

Med. Oral Pathol._ 59, 15–20 (1985). CAS  PubMed  Google Scholar  * Webster, L., Menzaghi, F. & Spencer, R. CR845, a novel peripherally-acting kappa opioid receptor agonist, has low

abuse potential compared with pentazocine. _J. Pain_ 16, S81 (2015). Google Scholar  * Spahn, V. et al. A nontoxic pain killer designed by modeling of pathological receptor conformations.

_Science_ 355, 966–969 (2017). CAS  PubMed  Google Scholar  * Milligan, G. The prevalence, maintenance, and relevance of G protein-coupled receptor oligomerization. _Mol. Pharmacol._ 84,

158–169 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Rozenfeld, R. & Devi, L. A. Receptor heteromerization and drug discovery. _Trends Pharmacol. Sci._ 31, 124–130 (2010). CAS

  PubMed  PubMed Central  Google Scholar  * Yekkirala, A. S. Two to tango: GPCR oligomers and GPCR–TRP channel interactions in nociception. _Life Sci._ 92, 438–445 (2013). CAS  PubMed 

Google Scholar  * Yekkirala, A. S., Kalyuzhny, A. E. & Portoghese, P. S. An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by

bivalent ligands. _ACS Chem. Biol._ 8, 1412–1416 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Lenard, N. R., Daniels, D. J., Portoghese, P. S. & Roerig, S. C. Absence of

conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. _Eur. J. Pharmacol._ 566, 75–82

(2007). CAS  PubMed  Google Scholar  * Aceto, M. D. et al. MDAN-21: a bivalent opioid ligand containing mu-agonist and delta-antagonist pharmacophores and its effects in rhesus monkeys.

_Int. J. Med. Chem._ 2012, 327257 (2012). PubMed  PubMed Central  Google Scholar  * Daniels, D. J. et al. Opioid-induced tolerance and dependence in mice is modulated by the distance between

pharmacophores in a bivalent ligand series. _Proc. Natl Acad. Sci. USA_ 102, 19208–19213 (2005). CAS  PubMed  Google Scholar  * Le Naour, M. et al. Bivalent ligands that target mu opioid

(MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. _J. Med. Chem._ 56, 5505–5513 (2013). CAS  PubMed  Google Scholar  * Akgun, E. et al. Ligands that interact

with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. _Proc. Natl Acad. Sci. USA_ 110, 11595–11599 (2013). CAS  PubMed  Google Scholar  * Akgun,

E. et al. Inhibition of inflammatory and neuropathic pain by targeting a mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5). _J. Med. Chem._ 58, 8647–8657 (2015). CAS  PubMed 

PubMed Central  Google Scholar  * Yekkirala, A. S. et al. N-Naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of mu/kappa-opioid heteromers. _Proc. Natl Acad. Sci.

USA_ 108, 5098–5103 (2011). CAS  PubMed  Google Scholar  * Chakrabarti, S., Liu, N. J. & Gintzler, A. R. Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates

female-specific opioid analgesia. _Proc. Natl Acad. Sci. USA_ 107, 20115–20119 (2010). CAS  PubMed  Google Scholar  * Ding, H. et al. A novel orvinol analog, BU08028, as a safe opioid

analgesic without abuse liability in primates. _Proc. Natl Acad. Sci. USA_ 113, E5511–E5518 (2016). CAS  PubMed  Google Scholar  * Pasternak, G. W. & Pan, Y. X. Mu opioids and their

receptors: evolution of a concept. _Pharmacol. Rev._ 65, 1257–1317 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Marrone, G. F. et al. Truncated mu opioid GPCR variant involvement

in opioid-dependent and opioid-independent pain modulatory systems within the CNS. _Proc. Natl Acad. Sci. USA_ 113, 3663–3668 (2016). CAS  PubMed  Google Scholar  * Majumdar, S. et al.

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. _Proc. Natl Acad. Sci. USA_ 108, 19778–19783

(2011). CAS  PubMed  Google Scholar  * Wieskopf, J. S. et al. Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene.

_Pain_ 155, 2063–2070 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Liu, X. Y. et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by

opioids. _Cell_ 147, 447–458 (2011). CAS  PubMed  PubMed Central  Google Scholar  * White, K. L. et al. The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique

spectrum of activities _in vivo_. _J. Pharmacol. Exp. Ther._ 352, 98–109 (2015). PubMed  PubMed Central  Google Scholar  * Tang, W., Strachan, R. T., Lefkowitz, R. J. & Rockman, H. A.

Allosteric modulation of beta-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch. _J. Biol. Chem._ 289, 28271–28283 (2014). CAS  PubMed  PubMed Central  Google

Scholar  * Drake, M. T. et al. β-Arrestin-biased agonism at the β2-adrenergic receptor. _J. Biol. Chem._ 283, 5669–5676 (2008). CAS  PubMed  Google Scholar  * Wisler, J. W., Xiao, K.,

Thomsen, A. R. & Lefkowitz, R. J. Recent developments in biased agonism. _Curr. Opin. Cell Biol._ 27, 18–24 (2014). IN THIS REVIEW, THE AUTHORS DESCRIBE HOW DIFFERENT LIGANDS CAN INDUCE

DISTINCT RECEPTOR CONFORMATIONS AT THE SAME GPCR TO ELICIT UNIQUE DOWNSTREAM SIGNALLING PROFILES. THEY PROVIDE SUPPORT FOR HOW THESE PROPERTIES COULD BE EXPLOITED TO DEVELOP ANALGESICS WITH

DIFFERENT OR REDUCED SIDE-EFFECT PROFILES. CAS  PubMed  Google Scholar  * Shukla, A. K. et al. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane

receptors. _Proc. Natl Acad. Sci. USA_ 105, 9988–9993 (2008). CAS  PubMed  Google Scholar  * Whalen, E. J., Rajagopal, S. & Lefkowitz, R. J. Therapeutic potential of beta-arrestin- and G

protein-biased agonists. _Trends Mol. Med._ 17, 126–139 (2011). CAS  PubMed  Google Scholar  * Zidar, D. A., Violin, J. D., Whalen, E. J. & Lefkowitz, R. J. Selective engagement of G

protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. _Proc. Natl Acad. Sci. USA_ 106, 9649–9654 (2009). CAS  PubMed  Google Scholar  * Gesty-Palmer, D. et

al. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. _Sci. Transl Med._ 1, 1ra1 (2009). PubMed  PubMed

Central  Google Scholar  * Strachan, R. T. et al. Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR). _J. Biol. Chem._ 289,

14211–14224 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Violin, J. D., Crombie, A. L., Soergel, D. G. & Lark, M. W. Biased ligands at G-protein-coupled receptors: promise and

progress. _Trends Pharmacol. Sci._ 35, 308–316 (2014). CAS  PubMed  Google Scholar  * Soergel, D. G. et al. Biased agonism of the mu-opioid receptor by TRV130 increases analgesia and reduces

on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. _Pain_ 155, 1829–1835 (2014). CAS  PubMed  Google Scholar 

* Soergel, D. G. et al. First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers. _J. Clin. Pharmacol._ 54, 351–357 (2014). CAS  PubMed  Google

Scholar  * Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. _Nature_ 537, 185–190 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Tabrizi,

M. A., Baraldi, P. G., Borea, P. A. & Varani, K. Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB2 receptor agonists. _Chem. Rev._ 116, 519–560

(2016). Google Scholar  * Han, S., Thatte, J., Buzard, D. J. & Jones, R. M. Therapeutic utility of cannabinoid receptor type 2 (CB2) selective agonists. _J. Med. Chem._ 56, 8224–8256

(2013). CAS  PubMed  Google Scholar  * Nevalainen, T. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. _Curr. Med. Chem._ 21, 187–203 (2014). CAS 

PubMed  Google Scholar  * Anand, U. et al. Mechanisms underlying clinical efficacy of angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and _in

vitro_ studies. _Mol. Pain_ 11, 38 (2015). PubMed  PubMed Central  Google Scholar  * Danser, A. H. & Anand, P. The angiotensin II type 2 receptor for pain control. _Cell_ 157, 1504–1506

(2014). CAS  PubMed  Google Scholar  * Rice, A. S. et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic

neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. _Lancet_ 383, 1637–1647 (2014). CAS  PubMed  Google Scholar  * Anand, U. et al. Angiotensin II type 2

receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. _Eur. J. Pain_ 17, 1012–1026 (2013). CAS 

PubMed  Google Scholar  * Smith, M. T., Woodruff, T. M., Wyse, B. D., Muralidharan, A. & Walther, T. A small molecule angiotensin II type 2 receptor (AT2R) antagonist produces analgesia

in a rat model of neuropathic pain by inhibition of p38 mitogen-activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia. _Pain Med._ 14, 1557–1568 (2013).

PubMed  Google Scholar  * Marion, E. et al. Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. _Cell_ 157, 1565–1576 (2014). CAS  PubMed  Google

Scholar  * Lemmens, S., Brone, B., Dooley, D., Hendrix, S. & Geurts, N. Alpha-adrenoceptor modulation in central nervous system trauma: pain, spasms, and paralysis — an unlucky triad.

_Med. Res. Rev._ 35, 653–677 (2015). CAS  PubMed  Google Scholar  * Giovannitti, J. A. Jr, Thoms, S. M. & Crawford, J. J. Alpha-2 adrenergic receptor agonists: a review of current

clinical applications. _Anesth. Prog._ 62, 31–39 (2015). PubMed  PubMed Central  Google Scholar  * Mori, K. et al. Effects of norepinephrine on rat cultured microglial cells that express

alpha1, alpha2, beta1 and beta2 adrenergic receptors. _Neuropharmacology_ 43, 1026–1034 (2002). CAS  PubMed  Google Scholar  * Lavand'homme, P. M. & Eisenach, J. C. Perioperative

administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. _Pain_

105, 247–254 (2003). CAS  PubMed  Google Scholar  * Feng, X. et al. Intrathecal administration of clonidine attenuates spinal neuroimmune activation in a rat model of neuropathic pain with

existing hyperalgesia. _Eur. J. Pharmacol._ 614, 38–43 (2009). CAS  PubMed  Google Scholar  * Wei, H. & Pertovaara, A. Spinal and pontine alpha2-adrenoceptors have opposite effects on

pain-related behavior in the neuropathic rat. _Eur. J. Pharmacol._ 551, 41–49 (2006). CAS  PubMed  Google Scholar  * Schnabel, A., Meyer-Friessem, C. H., Reichl, S. U., Zahn, P. K. &

Pogatzki-Zahn, E. M. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. _Pain_ 154, 1140–1149 (2013). CAS 

PubMed  Google Scholar  * Schnabel, A. et al. Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials.

_Paediatr. Anaesth._ 23, 170–179 (2013). PubMed  Google Scholar  * Melik Parsadaniantz, S., Rivat, C., Rostene, W. & Reaux-Le Goazigo, A. Opioid and chemokine receptor crosstalk: a

promising target for pain therapy? _Nat. Rev. Neurosci._ 16, 69–78 (2015). PubMed  Google Scholar  * Abbadie, C. et al. Chemokines and pain mechanisms. _Brain Res. Rev._ 60, 125–134 (2009).

CAS  PubMed  Google Scholar  * Reaux-Le Goazigo, A., Van Steenwinckel, J., Rostene, W. & Melik Parsadaniantz, S. Current status of chemokines in the adult CNS. _Prog. Neurobiol._ 104,

67–92 (2013). CAS  PubMed  Google Scholar  * Van Steenwinckel, J. et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain

after peripheral nerve injury. _J. Neurosci._ 31, 5865–5875 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Xie, F., Wang, Y., Li, X., Chao, Y. C. & Yue, Y. Early repeated

administration of CXCR4 antagonist AMD3100 dose-dependently improves neuropathic pain in rats after L5 spinal nerve ligation. _Neurochem. Res._ 41, 2289–2299 (2016). CAS  PubMed  Google

Scholar  * Talbot, S., Foster, S. L. & Woolf, C. J. Neuroimmunity: physiology and pathology. _Annu. Rev. Immunol._ 34, 421–447 (2016). CAS  PubMed  Google Scholar  * Szabo, I. et al.

Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. _Proc. Natl Acad. Sci. USA_ 99, 10276–10281 (2002). CAS  PubMed 

Google Scholar  * Szabo, I. et al. Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. _J. Leukoc. Biol._

74, 1074–1082 (2003). CAS  PubMed  Google Scholar  * Grimm, M. C. et al. Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. _J.

Exp. Med._ 188, 317–325 (1998). CAS  PubMed  PubMed Central  Google Scholar  * Pello, O. M. et al. Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for

immune response regulation. _Eur. J. Immunol._ 38, 537–549 (2008). CAS  PubMed  Google Scholar  * Rivat, C. et al. Src family kinases involved in CXCL12-induced loss of acute morphine

analgesia. _Brain Behav. Immun._ 38, 38–52 (2014). CAS  PubMed  Google Scholar  * Zhao, C. M. et al. Spinal MCP-1 contributes to the development of morphine antinociceptive tolerance in

rats. _Am. J. Med. Sci._ 344, 473–479 (2012). PubMed  Google Scholar  * Zhang, N., Rogers, T. J., Caterina, M. & Oppenheim, J. J. Proinflammatory chemokines, such as C-C chemokine ligand

3, desensitize mu-opioid receptors on dorsal root ganglia neurons. _J. Immunol._ 173, 594–599 (2004). CAS  PubMed  Google Scholar  * Ye, D. et al. Activation of CXCL10/CXCR3 signaling

attenuates morphine analgesia: involvement of Gi protein. _J. Mol. Neurosci._ 53, 571–579 (2014). CAS  PubMed  Google Scholar  * Rittner, H. L. et al. Pain control by CXCR2 ligands through

Ca2+-regulated release of opioid peptides from polymorphonuclear cells. _FASEB J._ 20, 2627–2629 (2006). CAS  PubMed  Google Scholar  * Wilson, N. M., Jung, H., Ripsch, M. S., Miller, R. J.

& White, F. A. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. _Brain Behav. Immun._ 25, 565–573 (2011). CAS  PubMed  Google Scholar  * Kalliomaki, J. et al. A

randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. _Pain_ 154, 761–767 (2013). PubMed  Google Scholar  * Padi, S. S.

et al. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. _Pain_ 153, 95–106

(2012). CAS  PubMed  Google Scholar  * Szallasi, A., Cortright, D. N., Blum, C. A. & Eid, S. R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist

proof-of-concept. _Nat. Rev. Drug Discov._ 6, 357–372 (2007). CAS  PubMed  Google Scholar  * Habib, A. M., Wood, J. N. & Cox, J. J. Sodium channels and pain. _Handb. Exp. Pharmacol._

227, 39–56 (2015). CAS  PubMed  Google Scholar  * Waxman, S. G. et al. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use.

_Lancet Neurol._ 13, 1152–1160 (2014). CAS  PubMed  Google Scholar  * Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. _Nature_ 389, 816–824

(1997). CAS  PubMed  Google Scholar  * Nilius, B. & Szallasi, A. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine.

_Pharmacol. Rev._ 66, 676–814 (2014). PubMed  Google Scholar  * Moran, M. M., McAlexander, M. A., Biro, T. & Szallasi, A. Transient receptor potential channels as therapeutic targets.

_Nat. Rev. Drug Discov._ 10, 601–620 (2011). CAS  PubMed  Google Scholar  * Carnevale, V. & Rohacs, T. TRPV1: a target for rational drug design. _Pharmaceuticals (Basel)_ 9, E52 (2016).

Google Scholar  * Lehto, S. G. et al. Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluorom ethyl)phenyl)-acrylamide (AMG8562), a

novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats. _J. Pharmacol. Exp. Ther._ 326, 218–229 (2008). CAS  PubMed  Google Scholar  *

Watabiki, T. et al. Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. _J. Pharmacol. Exp. Ther._

336, 743–750 (2011). CAS  PubMed  Google Scholar  * Chiche, D., Brown, W. & Walker, P. NEO6860, a novel modality selective TRPV1 antagonist: results from a phase I, double-blind,

placebo-controlled study in healthy subjects. _J. Pain_ 17, S79 (2016). Google Scholar  * Gao, Y., Cao, E., Julius, D. & Cheng, Y. TRPV1 structures in nanodiscs reveal mechanisms of

ligand and lipid action. _Nature_ 534, 347–351 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Cao, L. et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory

neurons and patients with inherited erythromelalgia. _Sci. Transl Med._ 8, 335ra56 (2016). PubMed  Google Scholar  * Dib-Hajj, S. D., Yang, Y., Black, J. A. & Waxman, S. G. The NaV1.7

sodium channel: from molecule to man. _Nat. Rev. Neurosci._ 14, 49–62 (2013). CAS  PubMed  Google Scholar  * Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to

experience pain. _Nature_ 444, 894–898 (2006). CAS  PubMed  Google Scholar  * Cox, J. J. et al. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. _Hum.

Mut._ 31, E1670–E1686 (2010). CAS  PubMed  Google Scholar  * Nassar, M. A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.

_Proc. Natl Acad. Sci. USA_ 101, 12706–12711 (2004). CAS  PubMed  Google Scholar  * Minett, M. S. et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and

sympathetic neurons. _Nat. Commun._ 3, 791 (2012). PubMed  PubMed Central  Google Scholar  * Gingras, J. et al. Global Nav1.7 knockout mice recapitulate the phenotype of human congenital

indifference to pain. _PLoS ONE_ 9, e105895 (2014). PubMed  PubMed Central  Google Scholar  * Bagal, S. K., Marron, B. E., Owen, R. M., Storer, R. I. & Swain, N. A. Voltage gated sodium

channels as drug discovery targets. _Channels (Austin)_ 9, 360–366 (2015). Google Scholar  * Sun, S., Cohen, C. J. & Dehnhardt, C. M. Inhibitors of voltage-gated sodium channel Nav1.7:

patent applications since 2010. _Pharm. Pat. Anal._ 3, 509–521 (2014). CAS  PubMed  Google Scholar  * Focken, T. et al. Discovery of aryl sulfonamides as isoform-selective inhibitors of

NaV1.7 with efficacy in rodent pain models. _ACS Med. Chem. Lett._ 7, 277–282 (2016). CAS  PubMed  PubMed Central  Google Scholar  * McCormack, K. et al. Voltage sensor interaction site for

selective small molecule inhibitors of voltage-gated sodium channels. _Proc. Natl Acad. Sci. USA_ 110, E2724–E2732 (2013). CAS  PubMed  Google Scholar  * Butt, M. et al. Morphologic,

stereologic, and morphometric evaluation of the nervous system in young cynomolgus monkeys (_Macaca fascicularis_) following maternal administration of tanezumab, a monoclonal antibody to

nerve growth factor. _Toxicol. Sci._ 142, 463–476 (2014). CAS  PubMed  Google Scholar  * Wainger, B. J. et al. Modeling pain _in vitro_ using nociceptor neurons reprogrammed from

fibroblasts. _Nat. Neurosci._ 18, 17–24 (2015). CAS  PubMed  Google Scholar  * Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. _Neuron_ 87, 341–354

(2015). CAS  PubMed  PubMed Central  Google Scholar  * Bauer, C. S. et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain

is inhibited by the alpha2delta ligand pregabalin. _J. Neurosci._ 29, 4076–4088 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Lawrence, J. Nav1.7: a new channel for pain treatment.

_Pharm. J._ http://dx.doi.org/10.1211/PJ.2016.20200841 (2016). * Bowman, C. J. et al. Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in

cynomolgus monkeys (_Macaca fascicularis_). _Reprod. Toxicol._ 53, 105–118 (2015). CAS  PubMed  Google Scholar  * Murray, J. K. et al. Single residue substitutions that confer voltage-gated

sodium ion channel subtype selectivity in the NaV1.7 inhibitory peptide GpTx-1. _J. Med. Chem._ 59, 2704–2717 (2016). CAS  PubMed  Google Scholar  * Weiss, J. et al. Loss-of-function

mutations in sodium channel Nav1.7 cause anosmia. _Nature_ 472, 186–190 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Minett, M. S. et al. Endogenous opioids contribute to

insensitivity to pain in humans and mice lacking sodium channel Nav1.7. _Nat. Commun._ 6, 8967 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Kort, M. E. et al. Subtype-selective

NaV1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives. _Bioorg. Med. Chem. Lett._ 20, 6812–6815 (2010). CAS  PubMed  Google Scholar  * Bagal, S. K.

et al. Recent progress in sodium channel modulators for pain. _Bioorg. Med. Chem. Lett._ 24, 3690–3699 (2014). CAS  PubMed  Google Scholar  * Wilson, M. J. et al. μ-Conotoxins that

differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. _Proc. Natl Acad. Sci. USA_ 108, 10302–10307 (2011). CAS  PubMed 

Google Scholar  * Rush, A. M., Cummins, T. R. & Waxman, S. G. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. _J. Physiol._ 579, 1–14

(2007). CAS  PubMed  Google Scholar  * Dib-Hajj, S. D., Black, J. A. & Waxman, S. G. NaV1.9: a sodium channel linked to human pain. _Nat. Rev. Neurosci._ 16, 511–519 (2015). CAS  PubMed

  Google Scholar  * Goral, R. O., Leipold, E., Nematian-Ardestani, E. & Heinemann, S. H. Heterologous expression of NaV1.9 chimeras in various cell systems. _Pflugers Arch._ 467,

2423–2435 (2015). CAS  PubMed  Google Scholar  * Owsianik, G., Talavera, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. _Annu. Rev. Physiol._ 68, 685–717 (2006).

CAS  PubMed  Google Scholar  * Hellwig, N. et al. TRPV1 acts as proton channel to induce acidification in nociceptive neurons. _J. Biol. Chem._ 279, 34553–34561 (2004). CAS  PubMed  Google

Scholar  * Meyers, J. R. et al. Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. _J. Neurosci._ 23, 4054–4065 (2003). CAS  PubMed  PubMed Central 

Google Scholar  * Binshtok, A. M., Bean, B. P. & Woolf, C. J. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. _Nature_ 449, 607–610 (2007). CAS 

PubMed  Google Scholar  * Puopolo, M. et al. Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314. _J. Neurophysiol._ 109, 1704–1712 (2013). CAS  PubMed  PubMed

Central  Google Scholar  * Brenneis, C. et al. Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block. _Br. J. Pharmacol._ 171, 438–451 (2014). CAS 

PubMed  Google Scholar  * Virginio, C., MacKenzie, A., Rassendren, F. A., North, R. A. & Surprenant, A. Pore dilation of neuronal P2X receptor channels. _Nat. Neurosci._ 2, 315–321

(1999). CAS  PubMed  Google Scholar  * Khakh, B. S., Bao, X. R., Labarca, C. & Lester, H. A. Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds. _Nat.

Neurosci._ 2, 322–330 (1999). CAS  PubMed  Google Scholar  * Yan, Z., Li, S., Liang, Z., Tomic, M. & Stojilkovic, S. S. The P2X7 receptor channel pore dilates under physiological ion

conditions. _J. Gen. Physiol._ 132, 563–573 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Binshtok, A. M. et al. Coapplication of lidocaine and the permanently charged sodium

channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. _Anesthesiology_ 111, 127–137 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Roberson, D. P.,

Binshtok, A. M., Blasl, F., Bean, B. P. & Woolf, C. J. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. _Br. J.

Pharmacol._ 164, 48–58 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Leffler, A. et al. The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent

sensory neurons. _J. Clin. Invest._ 118, 763–776 (2008). PubMed  PubMed Central  Google Scholar  * Leffler, A., Lattrell, A., Kronewald, S., Niedermirtl, F. & Nau, C. Activation of TRPA1

by membrane permeable local anesthetics. _Mol. Pain_ 7, 62 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Roberson, D. P. et al. Activity-dependent silencing reveals functionally

distinct itch-generating sensory neurons. _Nat. Neurosci._ 16, 910–918 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Zamponi, G. W., Striessnig, J., Koschak, A. & Dolphin, A. C.

The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. _Pharmacol. Rev._ 67, 821–870 (2015). CAS  PubMed  PubMed Central 

Google Scholar  * Zamponi, G. W. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. _Nat. Rev. Drug Discov._ 15, 19–34 (2016). IN THIS REVIEW, ZAMPONI

DISCUSSES VARIOUS CHALLENGES AND OPPORTUNITIES FOR USING CALCIUM CHANNELS AS DRUG TARGETS FOR NEUROLOGICAL DISORDERS. CAS  PubMed  Google Scholar  * Abbadie, C. et al. Analgesic effects of a

substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker. _J. Pharmacol. Exp. Ther._ 334, 545–555 (2010). CAS  PubMed  Google Scholar  * Patel,

R. et al. Electrophysiological characterization of activation state-dependent CaV2 channel antagonist TROX-1 in spinal nerve injured rats. _Neuroscience_ 297, 47–57 (2015). CAS  PubMed 

PubMed Central  Google Scholar  * Shao, P. P. et al. Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain. _J. Med. Chem._ 55, 9847–9855 (2012). CAS 

PubMed  Google Scholar  * Lipscombe, D. & Andrade, A. Calcium channel CaVα1 splice isoforms — tissue specificity and drug action. _Curr. Mol. Pharmacol._ 8, 22–31 (2015). CAS  PubMed 

PubMed Central  Google Scholar  * Bourinet, E. et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. _EMBO J._ 24, 315–324

(2005). CAS  PubMed  Google Scholar  * Choi, S. et al. Attenuated pain responses in mice lacking CaV3.2 T-type channels. _Genes Brain Behav._ 6, 425–431 (2007). CAS  PubMed  Google Scholar

  * Jarvis, M. F. et al. A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. _Biochem. Pharmacol._ 89,

536–544 (2014). CAS  PubMed  Google Scholar  * Wallace, M., Duan, R., Liu, W., Locke, C. & Nothaft, W. A. Randomized, double-blind, placebo-controlled, crossover study of the T-type

calcium channel blocker ABT-639 in an intradermal capsaicin experimental pain model in healthy adults. _Pain Med._ 17, 551–560 (2015). PubMed  Google Scholar  * Ziegler, D., Duan, W. R., An,

G., Thomas, J. W. & Nothaft, W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral

neuropathic pain. _Pain_ 156, 2013–2020 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Francois, A. et al. State-dependent properties of a new T-type calcium channel blocker enhance

CaV3.2 selectivity and support analgesic effects. _Pain_ 154, 283–293 (2013). CAS  PubMed  Google Scholar  * Xu, J. et al. A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and

spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain. _J. Neurophysiol._ 111, 394–404 (2014). CAS  PubMed  Google Scholar  * Zhu, C. Z. et al.

Mechanistic insights into the analgesic efficacy of A-1264087, a novel neuronal Ca2+ channel blocker that reduces nociception in rat preclinical pain models. _J. Pain_ 387, e1–e14 (2014).

Google Scholar  * Scott, V. E. et al. A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering

hemodynamic function in rats. _Biochem. Pharmacol._ 83, 406–418 (2012). CAS  PubMed  Google Scholar  * Marsh, B., Acosta, C., Djouhri, L. & Lawson, S. N. Leak K+ channel mRNAs in dorsal

root ganglia: relation to inflammation and spontaneous pain behaviour. _Mol. Cell. Neurosci._ 49, 375–386 (2012). CAS  PubMed  Google Scholar  * Pollema-Mays, S. L., Centeno, M. V., Ashford,

C. J., Apkarian, A. V. & Martina, M. Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. _Mol. Cell. Neurosci._ 57,

1–9 (2013). CAS  PubMed  Google Scholar  * Zheng, Q. et al. Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain

in a rat model. _Pain_ 154, 434–448 (2013). CAS  PubMed  Google Scholar  * Laumet, G. et al. G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain

transition. _Nat. Neurosci._ 18, 1746–1755 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Lu, R. et al. Slack channels expressed in sensory neurons control neuropathic pain in mice.

_J. Neurosci._ 35, 1125–1135 (2015). PubMed  PubMed Central  Google Scholar  * Lyu, C. et al. G protein-gated inwardly rectifying potassium channel subunits 1 and 2 are down-regulated in rat

dorsal root ganglion neurons and spinal cord after peripheral axotomy. _Mol. Pain_ 11, 44 (2015). PubMed  PubMed Central  Google Scholar  * Maljevic, S. & Lerche, H. Potassium channels:

a review of broadening therapeutic possibilities for neurological diseases. _J. Neurol._ 260, 2201–2211 (2013). CAS  PubMed  Google Scholar  * Tsantoulas, C. & McMahon, S. B. Opening

paths to novel analgesics: the role of potassium channels in chronic pain. _Trends Neurosci._ 37, 146–158 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Tsantoulas, C. Emerging

potassium channel targets for the treatment of pain. _Curr. Opin. Support. Palliat. Care_ 9, 147–154 (2015). PubMed  Google Scholar  * Wickenden, A. D. & McNaughton-Smith, G. Kv7

channels as targets for the treatment of pain. _Curr. Pharm. Des._ 15, 1773–1798 (2009). CAS  PubMed  Google Scholar  * Wu, Y. J. et al. Discovery of

(S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain. _Bioorg. Med. Chem. Lett._

23, 6188–6191 (2013). CAS  PubMed  Google Scholar  * Zheng, Y. et al. Activation of peripheral KCNQ channels relieves gout pain. _Pain_ 156, 1025–1035 (2015). CAS  PubMed  PubMed Central 

Google Scholar  * Mathie, A. & Veale, E. L. Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain. _Pflugers Arch._ 467, 931–943 (2015). CAS  PubMed

  Google Scholar  * Wang, H. S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. _Science_ 282, 1890–1893 (1998). CAS  PubMed  Google Scholar  * Pan,

Z. et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. _J. Neurosci._ 26, 2599–2613 (2006). CAS  PubMed  PubMed Central 

Google Scholar  * Cooper, E. C. Made for “anchorin”: Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons. _Semin. Cell Dev. Biol._ 22, 185–192

(2011). CAS  PubMed  Google Scholar  * Blackburn-Munro, G. & Jensen, B. S. The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic

pain. _Eur. J. Pharmacol._ 460, 109–116 (2003). CAS  PubMed  Google Scholar  * Li, H. et al. Antinociceptive efficacy of retigabine in the monosodium lodoacetate rat model for osteoarthritis

pain. _Pharmacology_ 95, 251–257 (2015). CAS  PubMed  Google Scholar  * Rose, K. et al. Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. _Pain_ 152,

742–754 (2011). CAS  PubMed  PubMed Central  Google Scholar  * King, C. H., Lancaster, E., Salomon, D., Peles, E. & Scherer, S. S. Kv7.2 regulates the function of peripheral sensory

neurons. _J. Comp. Neurol._ 522, 3262–3280 (2014). CAS  PubMed  PubMed Central  Google Scholar  * King, C. H. & Scherer, S. S. Kv7.5 is the primary Kv7 subunit expressed in C-fibers. _J.

Comp. Neurol._ 520, 1940–1950 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Feliciangeli, S., Chatelain, F. C., Bichet, D. & Lesage, F. The family of K2P channels: salient

structural and functional properties. _J. Physiol._ 593, 2587–2603 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Busserolles, J., Tsantoulas, C., Eschalier, A. & Lopez Garcia,

J. A. Potassium channels in neuropathic pain: advances, challenges, and emerging ideas. _Pain_ 157 (Suppl. 1), S7–S14 (2016). PubMed  Google Scholar  * Devilliers, M. et al. Activation of

TREK-1 by morphine results in analgesia without adverse side effects. _Nat. Commun._ 4, 2941 (2013). PubMed  Google Scholar  * Bagriantsev, S. N. et al. A high-throughput functional screen

identifies small molecule regulators of temperature- and mechano-sensitive K2P channels. _ACS Chem. Biol._ 8, 1841–1851 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Rodrigues, N.

et al. Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel. _Eur. J. Med. Chem._ 75, 391–402 (2014).

CAS  PubMed  Google Scholar  * Bocksteins, E. & Snyders, D. J. Electrically silent Kv subunits: their molecular and functional characteristics. _Physiology (Bethesda)_ 27, 73–84 (2012).

CAS  Google Scholar  * Bocksteins, E. Kv5, Kv6, Kv8, and Kv9 subunits: no simple silent bystanders. _J. Gen. Physiol._ 147, 105–125 (2016). CAS  PubMed  PubMed Central  Google Scholar  *

Tsantoulas, C. et al. Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury. _J. Neurosci._ 32, 17502–17513 (2012). CAS 

PubMed  PubMed Central  Google Scholar  * Tsantoulas, C. et al. Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input. _Exp. Neurol._ 251,

115–126 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Bocksteins, E. et al. Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG

neurons. _Am. J. Physiol. Cell Physiol._ 296, C1271–C1278 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Stas, J. I., Bocksteins, E., Labro, A. J. & Snyders, D. J. Modulation of

closed-state inactivation in Kv2.1/Kv6.4 heterotetramers as mechanism for 4-AP induced potentiation. _PLoS ONE_ 10, e0141349 (2015). PubMed  PubMed Central  Google Scholar  * Knabl, J. et

al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. _Nature_ 451, 330–334 (2008). CAS  PubMed  Google Scholar  * Bonin, R. P. & De Koninck, Y. Restoring

ionotropic inhibition as an analgesic strategy. _Neurosci Lett._ 557, 43–51 (2013). CAS  PubMed  Google Scholar  * Klinger, F. et al. δ subunit-containing GABAA receptors are preferred

targets for the centrally acting analgesic flupirtine. _Br. J. Pharmacol._ 172, 4946–4958 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Zeilhofer, H. U., Ralvenius, W. T. &

Acuna, M. A. Restoring the spinal pain gate: GABAA receptors as targets for novel analgesics. _Adv. Pharmacol._ 73, 71–96 (2015). CAS  PubMed  Google Scholar  * Tegeder, I. et al. GTP

cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. _Nat. Med._ 12, 1269–1277 (2006). CAS  PubMed  Google Scholar  * Latremoliere, A. et al. Reduction of

neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway. _Neuron_ 86, 1393–1406 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Chidley, C., Haruki,

H., Pedersen, M. G., Muller, E. & Johnsson, K. A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. _Nat. Chem. Biol._ 7, 375–383 (2011). CAS 

PubMed  Google Scholar  * Chandrasekhar, S. et al. Identification and characterization of novel microsomal prostaglandin E synthase-1 inhibitors for analgesia. _J. Pharmacol. Exp. Ther._

356, 635–644 (2016). CAS  PubMed  Google Scholar  * Jin, Y. et al. Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin E synthase 1 inhibitor, with celecoxib. _Clin.

Pharmacol. Ther._ 99, 274–284 (2016). CAS  PubMed  Google Scholar  * Wagner, K., Yang, J., Inceoglu, B. & Hammock, B. D. Soluble epoxide hydrolase inhibition is antinociceptive in a

mouse model of diabetic neuropathy. _J. Pain_ 15, 907–914 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Inceoglu, B. et al. Endoplasmic reticulum stress in the peripheral nervous

system is a significant driver of neuropathic pain. _Proc. Natl Acad. Sci. USA_ 112, 9082–9087 (2015). CAS  PubMed  Google Scholar  * Sisignano, M. et al. 5,6-EET is released upon neuronal

activity and induces mechanical pain hypersensitivity via TRPA1 on central afferent terminals. _J. Neurosci._ 32, 6364–6372 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Brenneis,

C. et al. Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation. _Mol. Pain_ 7, 78 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Lam, D. K., Dang, D., Zhang,

J., Dolan, J. C. & Schmidt, B. L. Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2. _J. Neurosci._ 32, 14178–14183 (2012). CAS  PubMed  PubMed Central 

Google Scholar  * Christianson, C. A. et al. Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism. _Neuroscience_ 200, 199–210

(2012). CAS  PubMed  Google Scholar  * Berta, T. et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion. _J. Clin. Invest._ 124, 1173–1186 (2014).

CAS  PubMed  PubMed Central  Google Scholar  * Clark, A. K., Grist, J., Al-Kashi, A., Perretti, M. & Malcangio, M. Spinal cathepsin S and fractalkine contribute to chronic pain in the

collagen-induced arthritis model. _Arthritis Rheum._ 64, 2038–2047 (2012). CAS  PubMed  Google Scholar  * Vicuna, L. et al. The serine protease inhibitor SerpinA3N attenuates neuropathic

pain by inhibiting T cell-derived leukocyte elastase. _Nat. Med._ 21, 518–523 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Landry, R. P., Jacobs, V. L., Romero-Sandoval, E. A.

& DeLeo, J. A. Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: _in vitro_ evidence for differential responses in human and rodent

microglia and macrophages. _Exp. Neurol._ 234, 340–350 (2012). CAS  PubMed  Google Scholar  * Ji, R. R. Mitogen-activated protein kinases as potential targets for pain killers. _Curr. Opin.

Investig. Drugs_ 5, 71–75 (2004). PubMed  Google Scholar  * Ostenfeld, T. et al. A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor,

losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy. _Clin. J. Pain_ 31, 283–293 (2015). PubMed  Google Scholar  * Smith, M. T., Wyse, B. D. & Edwards, S. R.

Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats. _Pain

Med._ 14, 692–705 (2013). PubMed  Google Scholar  * Bevan, S., Quallo, T. & Andersson, D. A. TRPV1. _Handb. Exp. Pharmacol._ 222, 207–245 (2014). CAS  PubMed  Google Scholar  * Girardin,

F. Membrane transporter proteins: a challenge for CNS drug development. _Dialogues Clin. Neurosci._ 8, 311–321 (2006). PubMed  PubMed Central  Google Scholar  * Huggins, J. P., Smart, T.

S., Langman, S., Taylor, L. & Young, T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which

modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. _Pain_ 153, 1837–1846 (2012). CAS  PubMed  Google Scholar  *

Keith, J. M. et al. Preclinical characterization of the FAAH inhibitor JNJ-42165279. _ACS Med. Chem. Lett._ 6, 1204–1208 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Pawsey, S. et

al. Safety, tolerability and pharmacokinetics of FAAH inhibitor V158866: a double-blind, randomised, placebo-controlled phase I study in healthy volunteers. _Drugs R. D_ 16, 181–191 (2016).

CAS  PubMed  PubMed Central  Google Scholar  * Cajanus, K. et al. Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women

treated for breast cancer. _Pain_ 157, 361–369 (2016). CAS  PubMed  Google Scholar  * Woolf, C. J., Safieh-Garabedian, B., Ma, Q. P., Crilly, P. & Winter, J. Nerve growth factor

contributes to the generation of inflammatory sensory hypersensitivity. _Neuroscience_ 62, 327–331 (1994). CAS  PubMed  Google Scholar  * Gimbel, J. S. et al. Long-term safety and

effectiveness of tanezumab as treatment for chronic low back pain. _Pain_ 155, 1793–1801 (2014). CAS  PubMed  Google Scholar  * Bramson, C. et al. Exploring the role of tanezumab as a novel

treatment for the relief of neuropathic pain. _Pain Med._ 16, 1163–1176 (2015). PubMed  Google Scholar  * Schnitzer, T. J. & Marks, J. A. A systematic review of the efficacy and general

safety of antibodies to NGF in the treatment of OA of the hip or knee. _Osteoarthritis Cartilage_ 23 (Suppl. 1), S8–S17 (2015). PubMed  Google Scholar  * Hochberg, M. C. et al. When is

osteonecrosis not osteonecrosis? Adjudication of reported serious adverse joint events in the tanezumab clinical development program. _Arthritis Rheumatol._ 68, 382–391 (2016). CAS  PubMed 

Google Scholar  * Sorge, R. E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. _Nat. Methods_ 11, 629–632 (2014). CAS  PubMed  Google

Scholar  * Baron, R. et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. _Pain_ 158, 261–272 (2016). PubMed Central  Google Scholar  *

Mogil, J. S., Davis, K. D. & Derbyshire, S. W. The necessity of animal models in pain research. _Pain_ 151, 12–17 (2010). IN THIS REVIEW, MOGIL AND COLLEAGUES DESCRIBE THE CRUCIAL ROLE

OF ANIMAL MODELS IN THE DEVELOPMENT OF CLINICAL ANALGESICS AND PROPOSE ADVANCEMENTS IN ANIMAL MODELS OF PAIN THAT COULD IMPROVE THE RELEVANCE AND TRANSLATABILITY OF PRECLINICAL STUDIES.

PubMed  Google Scholar  * Whiteside, G. T., Pomonis, J. D. & Kennedy, J. D. An industry perspective on the role and utility of animal models of pain in drug discovery. _Neurosci. Lett._

557, 65–72 (2013). CAS  PubMed  Google Scholar  * Hill, R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? _Trends Pharmacol. Sci._ 21, 244–246 (2000). CAS 

PubMed  Google Scholar  * Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. _Nat. Neurosci._ 18, 1081–1083 (2015). CAS  PubMed 

PubMed Central  Google Scholar  * Edwards, R. R., Dworkin, R. H., Sullivan, M. D., Turk, D. C. & Wasan, A. D. The role of psychosocial processes in the development and maintenance of

chronic pain. _J. Pain_ 17, T70–T92 (2016). PubMed  PubMed Central  Google Scholar  * Smith, S. M. et al. Pain intensity rating training: results from an exploratory study of the ACTTION

PROTECCT system. _Pain_ 157, 1056–1064 (2016). PubMed  Google Scholar  * Dodd, S., Dean, O. M., Vian, J. & Berk, M. A. Review of the theoretical and biological understanding of the

nocebo and placebo phenomena. _Clin. Ther._ 39, 469–476 (2017). PubMed  Google Scholar  * Paice, J. A. et al. AAPT diagnostic criteria for chronic cancer pain conditions. _J. Pain_ 18,

233–246 (2017). PubMed  Google Scholar  * Smith, S. M. et al. The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials:

IMMPACT considerations. _J. Pain_ http://dx.doi.org/10.1016/j.jpain.2017.02.429 (2017). * Edwards, R. R. et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT

recommendations. _Pain_ 157, 1851–1871 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Viscusi, E. R. et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the

mu-opioid receptor, for the intravenous treatment of acute pain. _Pain_ 157, 264–272 (2016). CAS  PubMed  Google Scholar  * Lu, Z. et al. Mediation of opioid analgesia by a truncated

6-transmembrane GPCR. _J. Clin. Invest._ 125, 2626–2630 (2015). PubMed  PubMed Central  Google Scholar  * Moriconi, A. et al. Targeting the minor pocket of C5aR for the rational design of an

oral allosteric inhibitor for inflammatory and neuropathic pain relief. _Proc. Natl Acad. Sci. USA_ 111, 16937–16942 (2014). CAS  PubMed  Google Scholar  * Altun, A. et al. Attenuation of

morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. _J. Physiol. Sci._ 65, 407–415 (2015). CAS  PubMed  Google Scholar  * Haugh, O., Penman, J., Irving, A. J.

& Campbell, V. A. The emerging role of the cannabinoid receptor family in peripheral and neuro-immune interactions. _Curr. Drug Targets_ 17, 1834–1840 (2016). CAS  PubMed  Google

Scholar  * Deliu, E. et al. The lysophosphatidylinositol receptor GPR55 modulates pain perception in the periaqueductal gray. _Mol. Pharmacol._ 88, 265–272 (2015). CAS  PubMed  PubMed

Central  Google Scholar  * Kort, M. E. & Kym, P. R. TRPV1 antagonists: clinical setbacks and prospects for future development. _Prog. Med. Chem._ 51, 57–70 (2012). CAS  PubMed  Google

Scholar  * Manitpisitkul, P. et al. Safety, tolerability and pharmacokinetic and pharmacodynamic learnings from a double-blind, randomized, placebo-controlled, sequential group

first-in-human study of the TRPV1 antagonist, JNJ-38893777, in healthy men. _Clin. Drug Investig._ 35, 353–363 (2015). CAS  PubMed  Google Scholar  * Quiding, H. et al. TRPV1 antagonistic

analgesic effect: a randomized study of AZD1386 in pain after third molar extraction. _Pain_ 154, 808–812 (2013). CAS  PubMed  Google Scholar  * De Petrocellis, L. & Moriello, A. S.

Modulation of the TRPV1 channel: current clinical trials and recent patents with focus on neurological conditions. _Recent Pat. CNS Drug Discov._ 8, 180–204 (2013). CAS  PubMed  Google

Scholar  * Ghosh, S. et al. Full fatty acid amide hydrolase inhibition combined with partial monoacylglycerol lipase inhibition: augmented and sustained antinociceptive effects with reduced

cannabimimetic side effects in mice. _J. Pharmacol. Exp. Ther._ 354, 111–120 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Grim, T. W. et al. Combined inhibition of FAAH and COX

produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. _Pharmacol. Biochem. Behav._ 124, 405–411 (2014). CAS  PubMed  PubMed Central  Google Scholar  *

Starowicz, K. et al. Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism.

_PLoS ONE_ 8, e60040 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Schlosburg, J. E. et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the

endocannabinoid system. _Nat. Neurosci._ 13, 1113–1119 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Luz, J. G. et al. Crystal structures of mPGES-1 inhibitor complexes form a basis

for the rational design of potent analgesic and anti-inflammatory therapeutics. _J. Med. Chem._ 58, 4727–4737 (2015). CAS  PubMed  Google Scholar  * Leclerc, P. et al. Characterization of a

human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation. _Prostaglandins Other Lipid Mediat._ 107, 26–34 (2013). CAS  PubMed  Google

Scholar  * Sjogren, T. et al. Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily. _Proc. Natl Acad. Sci. USA_ 110, 3806–3811

(2013). PubMed  Google Scholar  * Hellio le Graverand, M. P. et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat

(SD-6010), in patients with symptomatic osteoarthritis of the knee. _Ann. Rheum. Dis._ 72, 187–195 (2013). PubMed  Google Scholar  * Wozniak, K. M. et al. The orally active glutamate

carboxypeptidase II inhibitor E2072 exhibits sustained nerve exposure and attenuates peripheral neuropathy. _J. Pharmacol. Exp. Ther._ 343, 746–754 (2012). CAS  PubMed  Google Scholar  *

Vornov, J. J. et al. Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism.

_J. Pharmacol. Exp. Ther._ 346, 406–413 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Huang, J. L., Chen, X. L., Guo, C. & Wang, Y. X. Contributions of spinal D-amino acid

oxidase to bone cancer pain. _Amino Acids_ 43, 1905–1918 (2012). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors acknowledge generous funding support from the

following US National Institutes of Health grants: NS039518 and NS038253 (US National Institute of Neurological Disorders and Stroke (NINDS) to C.J.W); NS072040 and NS036855 (NINDS to

B.P.B.); and DA041912 (US National Institute on Drug Abuse to A.S.Y.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neurobiology, Harvard Medical School, Boston

Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA Ajay S. Yekkirala, David P. Roberson, Bruce P. Bean & Clifford J. Woolf * FM Kirby Neurobiology Center

Boston Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA Ajay S. Yekkirala, David P. Roberson & Clifford J. Woolf * Blue Therapeutics, Harvard Innovation

Launch Lab, 114 Western Avenue, Allston, 02134, Massachusetts, USA Ajay S. Yekkirala & David P. Roberson Authors * Ajay S. Yekkirala View author publications You can also search for this

author inPubMed Google Scholar * David P. Roberson View author publications You can also search for this author inPubMed Google Scholar * Bruce P. Bean View author publications You can also

search for this author inPubMed Google Scholar * Clifford J. Woolf View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence

to Ajay S. Yekkirala or Clifford J. Woolf. ETHICS DECLARATIONS COMPETING INTERESTS A.S.Y and D.P.R. are co-founders of Blue Therapeutics in Allston, Massachusetts, USA, which is focused on

developing non-addictive painkillers targeting G-protein-coupled receptor heteromers. A.S.Y. holds a patent on an analgesic agent. B.P.B. is a co-founder of Flex Pharma in Boston,

Massachusetts, USA, and co-holds patents on using charged sodium channel blockers for pain relief and other indications. C.J.W is co-founder and scientific advisor to Quartet Medicine in

Cambridge, Massachusetts, USA, which is focused on developing treatments for chronic pain and inflammation targeting the tetrahydrobiopterin pathway; he is also a consultant and stock holder

for Abide Therapeutics in San Diego, California, USA, and holds several patents related to methods and approaches for studying and treating pain. RELATED LINKS DATABASES ClinicalTrials.gov

FURTHER INFORMATION Arena Pharmaceuticals press release on APD371 BioTuesdays — Xenon still committed to TV-45070 for neuropathic pain Cara Therapeutics — Kappa Opioid Receptor Agonists

CNV2197944 phase II trial announcement press release CR845 phase IIa results press release CR845 phase III patient recruitment press release DEX-IN phase II efficacy press release DEX-IN

phase II side effects press release US Centers for Disease Control and Prevention — Overdose Xenon and Genentech collaboration press release Z944 phase Ib results press release POWERPOINT

SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR TABLE 2 POWERPOINT SLIDE FOR TABLE 3 GLOSSARY * Analgesics Pharmacological

agents or ligands that produce analgesia. * Tolerance A state in which the drug no longer produces the same effect and a higher dose is therefore needed. * Dependence An adaptive state that

develops when a pharmacological agent is used repeatedly and leads to withdrawal on cessation of the drug regimen. * Hyperalgesia Enhanced nociceptive response to a noxious stimulus, leading

to greater discomfort than before. * Allodynia Nociceptive response elicited even to previously non-noxious stimuli. * Phenocopy When an organism shows phenotypic characteristics that

reflect a different genotype from its own. * Neuropathic pain A condition leading to pain due to damage or disease of nervous system tissues. * Central sensitization A condition of the

nervous system in which neurons in the central nervous system are in a state of prolonged increase in excitability and synaptic efficacy, coupled with the loss of inhibitory activity. *

Analgesia A lack of, or insensibility to, pain. * Nociception Sensory neuronal responses to noxious or damaging stimuli that attribute the sensation of pain. * Depersonalization A state in

which an individual's thoughts, feelings and emotions seem to not belong to them. * Antinociception Inhibition of sensory neuronal response to noxious stimuli that leads to reduction of

pain sensation. * Ligand bias Occurs when a ligand shows selectivity or preference to a particular signal transduction mechanism for a target receptor. Also called 'functional

selectivity'. * Psychotomimetic effects A state of psychosis of the mind leading to delusions, hallucinations, and so on that are precipitated by a pharmacological agent or ligand. *

Post-herpetic neuralgia Pain caused by nerve damage due to infection with varicella zoster virus. * Withdrawal Symptoms such as anxiety and shaking that develop on cessation of a drug that

has been used repeatedly. * Trigeminal neuralgia A painful condition caused by disease affecting, dysfunction of or damage to the trigeminal nerve. * Anosmia Loss of the sense of smell. *

Allosteric modulators Ligands that alter the activity of an agonist, antagonist or inverse agonist of a target by binding to a site distinct from the active site. * Phenotypic screens

Unbiased screening strategies in which the functional output is a pre-determined alteration of phenotype. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Yekkirala, A., Roberson, D., Bean, B. _et al._ Breaking barriers to novel analgesic drug development. _Nat Rev Drug Discov_ 16, 545–564 (2017). https://doi.org/10.1038/nrd.2017.87 Download

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