Skip to main content
SpringerLink
Log in

Analgesic targets: today and tomorrow

  • Review
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Pain is recognized as a multifactorial sensory experience that is wholly unpleasant. It can vary in intensity from mild to severe and its duration can be anything from transient to persistent. Today we know so much more about the peripheral nociceptor as the primary detection apparatus for painful stimuli. We also understand in far greater detail the neurochemical mechanisms that occur at the level of the spinal cord and the complex interplay that exists between excitatory and inhibitory neural pathways. As a consequence of the assembly of this new body of evidence there are clear pointers that direct our attention to receptors, signaling pathways, enzymes and ion channels that all have the potential to be targets for novel, effective analgesics. The purpose of this review is to highlight some of the knowledge that has been assembled on this subject in recent years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Agarwal N, Pacher P, Tegeder I, et al. Cannabinoid mediated analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;7:870–9.

    Article  CAS  Google Scholar 

  • Ahmadi S, Lippross S, Neuhuber WL, et al. PGE2 selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci. 2002;5:34–40.

    Article  PubMed  CAS  Google Scholar 

  • Akopian AN, Sivilotti L, Wood JN, et al. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature. 1996;379:257–62.

    Article  PubMed  CAS  Google Scholar 

  • Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci. 2002;22:10277–90.

    PubMed  CAS  Google Scholar 

  • Bley KR. Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies. Expert Opin Investig Drugs. 2004;13:1445–56.

    Article  PubMed  CAS  Google Scholar 

  • Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist icatibant. J Allergy Clin Immunol. 2007;119:1497–503.

    Article  PubMed  CAS  Google Scholar 

  • Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–102.

    Article  PubMed  CAS  Google Scholar 

  • Brose WG, Gutlove DP, Luther RR, et al. Use of intrathecal SNX-111, a novel N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. Clin J Pain. 1997;13:256–9.

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–24.

    Article  PubMed  CAS  Google Scholar 

  • Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000;16:521–5.

    Article  PubMed  CAS  Google Scholar 

  • Chizh BA, O’Donnell MB, Napoltano A, et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain. 2007;132:132–41.

    Article  PubMed  CAS  Google Scholar 

  • Chuang H, Prescott ED, Kong H, et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition. Nature. 2001;411:957–62.

    Article  PubMed  CAS  Google Scholar 

  • Cockayne DA, Hamilton SG, Zhu Q-M, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407:1011–5.

    Article  PubMed  CAS  Google Scholar 

  • Coggeshall RE, Tate S, Carlton SM, et al. Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats. Neurosci Lett. 2004;355:45–8.

    Article  PubMed  CAS  Google Scholar 

  • Coull JAM, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017–21.

    Article  PubMed  CAS  Google Scholar 

  • Dray A. Neuropathic pain: emerging treatments. Br J Anaesth. 2008;101:48–58.

    Article  PubMed  CAS  Google Scholar 

  • Feletou M, Germain M, Thurieau C, et al. Agonistic and antagonistic properties of the bradykinin B2 receptor antagonist, Hoe 140, in isolated blood vessels from different species. Br J Pharmacol. 1994;112:683–9.

    PubMed  CAS  Google Scholar 

  • FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cycloxygenase-2. N Engl J Med. 2001;345:433–42.

    Article  PubMed  CAS  Google Scholar 

  • Fox A, Bevan S. Therapeutic potential of cannabinoid receptor agonists as analgesic agents. Expert Opin Investig Drugs. 2005;14:695–703.

    Article  PubMed  CAS  Google Scholar 

  • Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871–4.

    Article  PubMed  CAS  Google Scholar 

  • Gogas KR. Glutamate therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol. 2006;6:68–74.

    Article  PubMed  CAS  Google Scholar 

  • Gold MS, Weinreich D, Kim CS, et al. Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci. 2003;23:158–66.

    PubMed  CAS  Google Scholar 

  • Goldin AL. Resurgence of sodium channel research. Annu Rev Physiol. 2001;63:871–94.

    Article  PubMed  CAS  Google Scholar 

  • Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4–15.

    Article  PubMed  CAS  Google Scholar 

  • Harvey RJ, Depner UB, Wassle H, et al. Glyα3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science. 2004;304:884–7.

    Article  PubMed  CAS  Google Scholar 

  • Jarvis MF, Honore P, Shieh C-C, 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. 2007;104:8520–5.

    Article  PubMed  CAS  Google Scholar 

  • Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203–10.

    Article  PubMed  CAS  Google Scholar 

  • Kang M-G, Felix R, Campbell KP, et al. Long term regulation of voltage-gated Ca2+ channels by gabapentin. FEBS Lett. 2002;528:177–82.

    Article  PubMed  CAS  Google Scholar 

  • Kim C, Jun K, Lee T, et al. Altered nociceptive responses in mice deficient in the α1δ subunit of the voltage-dependent calcium channel. Mol Cell Neurosci. 2001;18:235–45.

    Article  PubMed  CAS  Google Scholar 

  • Knabl J, Witschi R, Hosl K, et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature. 2008;451:330–4.

    Article  PubMed  CAS  Google Scholar 

  • Lane N, Webster L, Shiao-Ping L, et al. RN624 (anti NGF) improves pain and function in subjects with moderate knee osteoarthritis: a phase I study. Arthritis Rheum. 2005;52:S461.

    Article  Google Scholar 

  • Liu XJ, Gingrich JR, Vargas-Caballero M, et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nature. 2008;14:1325–32.

    Article  CAS  Google Scholar 

  • Luo ZD, Chaplan SR, Higuera ES, et al. Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001;21:1868–75.

    PubMed  CAS  Google Scholar 

  • Luo ZD, Calcutt NA, Higuera ES, et al. Injury type-specific channel α2δ-1 subunit upregulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther. 2002;303:1199–205.

    Article  PubMed  CAS  Google Scholar 

  • McGaraughty S, Jarvis MF. Antinociceptive properties of a non-nucleotide P2X3/P2X2/3 receptor antagonist. Drug News Perspect. 2005;18:501–7.

    Article  PubMed  CAS  Google Scholar 

  • McGuire D, Bowersox S, Fellmann JD, et al. Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans. J Cardiovasc Pharmacol. 1997;30:400–3.

    Article  PubMed  CAS  Google Scholar 

  • Merskey H, Bogduk N. Classification of chronic pain. Seattle: IASP Press; 1994. p. 210.

    Google Scholar 

  • Mitchell JA, Warner TD. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov. 2006;5:75–85.

    Article  PubMed  CAS  Google Scholar 

  • Moore KA, Kohno T, Karchewski LA, et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci. 2002;22:6724–31.

    PubMed  CAS  Google Scholar 

  • Nurmikko TJ, Serpell MG, Hoggat B, et al. Savitex successfully treats neuropathic pain characterized by allodynia: a randomized, double blind, placebo-controlled clinical trial. Pain. 2007;133:210–20.

    Article  PubMed  CAS  Google Scholar 

  • Owolabi JB, Rizkalla G, Tehim A, et al. Characterization of anti-allodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat. J Pharmacol Exp Ther. 1999;289:1271–6.

    PubMed  CAS  Google Scholar 

  • Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov. 2009;8:55–68.

    Article  PubMed  CAS  Google Scholar 

  • Ramer MS, Bradbury EJ, McMahon SB, et al. Nerve growth factor induces P2X(3) expression in sensory neurons. J Neurochem. 2001;77:864–75.

    Article  PubMed  CAS  Google Scholar 

  • Reinold H, Ahmadi S, Depner UB, et al. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Invest. 2005;115:673–9.

    PubMed  CAS  Google Scholar 

  • Riendeau D, Aspiotis R, Ethier D, et al. Inhibitors of the inducible microsomal prostaglandin E2 synthase (MPGES-1) derived from MK-886. Biorg Med Chem Lett. 2005;15:3352–5.

    Article  CAS  Google Scholar 

  • Samad TA, Sapirstein A, Woolf CJ, et al. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002;8:390–6.

    Article  PubMed  CAS  Google Scholar 

  • Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–8.

    Article  PubMed  CAS  Google Scholar 

  • Sharp CJ, Reeve AJ, Collins SD, et al. Investigation into the role of P2X3/P2X2/3 receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiology study. Br J Pharmacol. 2006;148:845–52.

    Article  PubMed  CAS  Google Scholar 

  • Sherrington CS. The integrative action of the nervous system. New York: Scribner; 1906.

    Google Scholar 

  • Snutch TP. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx. 2005;4:662–70.

    Article  Google Scholar 

  • Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291:63–70.

    Article  PubMed  CAS  Google Scholar 

  • Szallasi A, Cortright DN, Blum CA, et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev. 2007;6:357–72.

    Article  CAS  Google Scholar 

  • Tanaka M, Cummins TR, Ishikawa K, et al. SNS sodium channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport. 1998;9:967–72.

    Article  PubMed  CAS  Google Scholar 

  • Torsney C, MacDermott AB. A painful factor. Nature. 2005;438:923–5.

    Article  PubMed  CAS  Google Scholar 

  • Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778–83.

    Article  PubMed  CAS  Google Scholar 

  • Vega-Hernandez A, Felix R. Down-regulation of N-type-activated Ca2+ channels by gabapentin. Cell Mol Neurobiol. 2002;22:185–90.

    Article  PubMed  CAS  Google Scholar 

  • Vellani V, Zachrisson O, McNaughton PA. Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF. J Physiol. 2004;560:391–401.

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Woolf CJ. Pain TRPs. Neuron. 2005;46:9–12.

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Kohno T, Amaya F, et al. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J Neurosci. 2005;25:7986–92.

    Article  PubMed  CAS  Google Scholar 

  • Warner TD, Mitchell JA. COX-2 selectivity alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet. 2008;371:270–3.

    Article  PubMed  CAS  Google Scholar 

  • Winquist RJ, Pan JQ, Gribkoff VK. Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem Pharmacol. 2005;70(48):9–499.

    Google Scholar 

  • Wirth K, Hock FJ, Albus U, et al. Hoe 140, a new potent and long acting bradykinin-antagonist: in vivo studies. Br J Pharmacol. 1991;102:774–7.

    PubMed  CAS  Google Scholar 

  • Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441–51.

    PubMed  Google Scholar 

  • Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–8.

    Article  PubMed  CAS  Google Scholar 

  • Zeilhofer HU. The glycinergic control of spinal pain. Cell Mol Life Sci. 2005;62:2027–35.

    Article  PubMed  CAS  Google Scholar 

  • Zeilhofer HU, Brune K. Analgesic strategies beyond the inhibition of cyclooxygenases. Trends Pharmacol Sci. 2006;9:467–74.

    Article  CAS  Google Scholar 

  • Zimmermann K, Leffler A, Babes A, et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007;447(85):5–859.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St Joseph’s Healthcare Hamilton, Department of Medicine, Faculty of Health Sciences, McMaster University, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6, Canada

    Ian W. Rodger

Authors
  1. Ian W. Rodger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian W. Rodger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodger, I.W. Analgesic targets: today and tomorrow. Inflammopharmacol 17, 151–161 (2009). https://doi.org/10.1007/s10787-009-0006-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-009-0006-z

Keywords

Search

Navigation