It is perhaps presumptuous to talk about the molecular basis of a subjective sensation such as pain, but defined conformational changes in membrane proteins, controlled by a family of extra- and intracellular messenger molecules, are known to underlie the activation of sensory nerve terminals and the process of synaptic neurotransmission, which are necessary for pain perception. Furthermore, a subset of neurotransmission processes has a permissive, and possibly exclusive, role in pain perception. Clearly, the experience of pain in the clinical sense with all its affective components of unpleasantness and suffering cannot yet be fully understood in molecular terms, but the process of nociception, whereby the signal generated as a result of tissue damaging or potentially damaging peripheral stimuli reaches and evokes neuronal activity in the central nervous system, is becoming better characterized. Recent advances in neurobiology have given us insights that are already helping improve understanding of the events that lead to a patient experiencing pain and, it is hoped, will also lead to more successful treatment strategies.
Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, and others. 1999. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci2:541-548.
3.
Averbeck B, Izydorczyk I, Kress M.2000. Inflammatory mediators release calcitonin gene-related peptide from dorsal root ganglion neurons of the rat. Neuroscience98:135-140.
4.
Bennett GJ. 1999. Does a neuroimmune interaction contribute to the genesis of painful peripheral neuropathies?Proc Natl Acad Sci U SA96:7737-7738.
5.
Bordi F, Ugolini A.2000. Involvement of mGluR on acute nociceptive transmission. Brain Res871:223-233.
6.
Borkowski JA, Ransom RW, Seabrook GR, Trumbauer M, Chen H, Hill, RG, and others. 1995. Targeted disruption of a B bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J Biol Chem270:13706-13710.
7.
Boyce S, Hill RG. 2000. Discrepant results from preclinical and clinical studies on the potential of substance P-receptor antagonist compounds as analgesics. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z, editors. Proceedings of the 9th world congress on pain. Seattle: IASP Press. p 313-324.
8.
Brinkmeier H, Aulkemeyer P, Wollinsky KH, Rüdel R.2000. An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system. Nat Med6:808-811.
9.
Caterina MJ, Julius D.1999. Sense and specificity: a molecular identity for nociceptors. Curr Opin Neurobiol9:525-530.
10.
Cejas PJ, MartinezM, Karmally S, McKillop M, McKillop J, Plunkett JA, and others. 2000. Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction. Pain86:195-210.
11.
Cervero F, Laird JMA. 1991. One pain or many pains?NIPS6:268-273.
12.
Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN, Waxman SG. 1999. A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J Neurosci19: RC43(1-6).
13.
Hammond DL. 1997. Inhibitory neurotransmitters and nociception: role of GABA and glycine. In: Dickenson A, Besson JM, editors. Handbook of experimental pharmacology. Berlin: Springer. p 361-383.
14.
Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, and others. 1999. Functional consequences of mutations in the human α calcium channel subunit linked to familial hemiplegic migraine. J Neurosci19:1610-1619.
15.
Hatada Y, Wu F, Sun Z-Y, Schacher S, Goldberg DJ. 2000. Presynaptic morphological changes associated with long-term synaptic facilitation are triggered by actin polymerization at preexisting varicosities. J Neurosci20: RC82(1-5).
16.
Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SGN. 2000. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci3:661-669.
17.
Hutchison WD, Davis KD, Lozano AM, Tasker RR, Dostrovsky JO. 1999. Pain-related neurons in the human cingulate cortex. Nat Neurosci2:403-405.
18.
Hwang SW, Cho H, Kwak J, Lee S-Y, Kang C-J, Jung J, and others. 2000. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U SA97:6155-6160.
19.
Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. 1999. Brain-derived TNFα mediates neuropathic pain. Brain Res841:70-77.
20.
Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, and others. 1996. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet13:485-488.
21.
Ji R-R, Baba H, Brenner GJ, Woolf CJ. 1999. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci2:1114-1119.
22.
Jordt S-E, Tominaga M, Julius D.2000. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci U SA97:8134-8139.
23.
Joshi SK, Su X, Porreca F, Gebhart GF. 2000. k-opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action. J Neurosci20:5874-5929.
24.
Kerr BJ, Cafferty WBJ, Gupta YK, Bacon A, Wynick D, McMahon SB, and others. 2000. Galanin knockout mice reveal nociceptive deficits following peripheral nerve injury. Eur J Neurosci12:793-802.
25.
Kimura T, Komatsu T, Hosoda R, Nishiwaki K, Shimada Y. 2000. Angiotensin-converting enzyme gene polymorphism in patients with neuropathic pain. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z, editors. Proceedings of the 9th world congress on pain. Seattle: IASP Press. p 471-476.
26.
Levy D, Zochodne DW. 2000. Increased mRNA expression of the B and B bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain. Pain86:265-271.
27.
Lewis SE, Mannion RJ, White FA, Coggeshall RE, Beggs S, Costigan M, and others. 1999. A role for HSP27 in sensory neuron survival. J Neurosci19:8945-8953.
28.
Lindenlaub T, Teuteberg P, Hartung T, Sommer C.2000. Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res866:15-22.
29.
Mascia MP, Trudell JR, Harris RA. 2000. Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc Natl Acad Sci U SA97:9305-9310.
30.
Max M.1999. Pain 1999—an updated review. Seattle: IASP Press.
31.
McCarter GC, Reichling DB, Levine JD. 1999. Mechanical transduction by rat dorsal root ganglion neurons in vitro. Neurosci Lett273:179-182.
32.
McMahon SB, Bennett DLH. 2000. Glial cell line-derived neurotrophic factor and nociceptive neurons. In: Wood JN, editor. Molecular basis of pain induction. New York: Wiley-Liss. p 65-86.
33.
Milligan ED, Mehmert KK, Hinde JL, Harvey, Jr LO, Martin D, and others. 2000. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp 120. Brain Res861:105-116.
34.
Munglani R, Hill RG. 1999. Other drugs including sympathetic block. In: Wall PD, Melzack R, editors. Textbook of pain, 4th ed.Edinburgh, UK: Churchill Livingstone. p 1233-1250.
35.
Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, and others. 1999. Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science286:1558-1561.
36.
Ophoff RA, Terwindt GM, Frants RR, Ferrari MD. 1998. P/Q-type Ca channel defects in migraine, ataxia and epilepsy. Trends Pharmacol Sci19:121-126.
37.
Owolabi JB, Rizkalla G, Tehim A, Ross GM, Riopelle RJ, Kamboj R, and others. 1999. Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat. J Pharmacol Exp Ther289:1271-1276.
38.
Patel AJ, HonoréE, Lesage F, Fink M, RomeyG, Lazdunski M.1999. Inhalational anesthetics activate two-pore-domain background K channels. Nat Neurosci2:422-426.
39.
Perl ER. 1998. Getting a line on pain: is it mediated by dedicated pathways?Nat Neurosci1:177-178.
40.
Pesquero JB, Araujo RC, Heppenstall PA, Stucky CL, Silva, JA Jr, Walther T, and others. 2000. Hypoalgesia and altered inflammatory responses in mice lacking kinin B receptors. Proc Natl Acad Sci U SA97:8140-8145.
41.
Phagoo SB, Poole S, Leeb-Lundberg LMF. 1999. Autoregulation of bradykinin receptors: agonists in the presence of interleukin-1β shift the repertoire of receptor subtypes from B to B in human lung fibroblasts. Mol Pharmacol56:325-333.
42.
Porreca F, Lai J, Bian D, Wegert S, Ossipov MH, Eglen RM, and others. 1999. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U SA96:7640-7644.
43.
Reichling DB, Levine JD. 2000. In hot pursuit of the elusive heat transducers. Neuron26:555-558.
Rupniak NMJ, Boyce S, Webb JK, Williams AR, Carlson EJ, Hill RG, and others. 1997. Effects of the bradykinin B receptor antagonist des-Arg [Leu]bradykinin and genetic disruption of the B receptor on nociception in rats and mice. Pain71:89-97.
46.
Schmidt R, Schmelz M, Torebjörk HE, Handwerker HO. 2000. Mechano-insensitive nociceptors encode pain evoked by tonic pressure to human skin. Neuroscience98:793-800.
47.
Shu X-Q, Mendell LM. 1999. Neurotrophins and hyperalgesia. Proc Natl Acad Sci U SA96:7693-7696.
48.
Silos-Santiago I.2000. Neurotrophic signaling and sensory neuron survival and function. In: Wood JN, editor. Molecular basis of pain induction. New York: Wiley-Liss. p 43-63.
49.
Sten Shi T-J, Cui J-G, Meyerson BA, Linderoth B, Hökfelt T.1999. Regulation of galanin and neuropeptide Y in dorsal root ganglia and dorsal horn in rat mononeuropathic models: possible relation to tactile hypersensitivity. Neuroscience93:741-757.
50.
Stucky CL, Lewin GR. 1999. Isolectin B-positive and -negative nociceptors are functionally distinct. J Neurosci19:6497-6505.
51.
Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K.2000. Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X receptor signaling in capsaicin-insensitive primary afferent neurons. J Neurosci20: RC90(1-5).
52.
Walker JM, Huang SM, Strangman NM, Tsou K, Sañudo-Peña MC. 1999. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U SA96:12198-12203.
Waxman SG, Dib-Hajj S, Cummins TR, Black JA. 1999. Sodium channels and pain. Proc Natl Acad Sci U SA96:7635-7639.
55.
White DM, Walker S, Brenneman DE, Gozes I.2000. CREB contributes to the increased neurite outgrowth of sensory neurons induced by vasoactive intestinal polypeptide and activity-dependent neurotrophic factor. Brain Res868:31-38.
56.
Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. 1997. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia17:518-524.
57.
Wood JN. 2000. Molecular basis of pain induction. New York: Wiley-Liss.
58.
Woolf CJ, Salter MW. 2000. Neuronal plasticity: increasing the gain in pain. Science288:1765-1768.
Zimmer A, Usdin T.2000. Examination of the opioid system using targeted gene deletions. In: Wood JN, editor. Molecular basis of pain induction. New York: Wiley-Liss. p 193-207.
