国际口腔医学杂志 ›› 2025, Vol. 52 ›› Issue (4): 498-506.doi: 10.7518/gjkq.2025057
Jiashuo Zhao(),Yanyan Zhang,Fei Liu,Jiefei Shen(
)
摘要:
口颌面神经病理性疼痛的病理机制复杂,目前仍缺乏持久有效的治疗手段,给患者生活带来沉重负担。神经肽,包括甘丙肽、降钙素基因相关肽、神经肽Y、催产素等,通过不同信号通路调控伤害性信号传导,在神经病理性疼痛的病理过程中发挥重要的调控作用。目前神经肽在口颌面神经病理性疼痛中的作用和机制研究相对不足,针对神经肽作为口颌面神经病理性疼痛的治疗靶点尚缺乏充分的临床证据。本文回顾了上述4种常见的神经肽在外周及中枢神经系统中调控神经病理疼痛涉及的分子信号通路机制,为探究其在口颌面神经病理性疼痛中的作用和机制研究提供新思路,为研发新型镇痛药提供有效策略。
中图分类号:
1 | Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the international classification of diseases (ICD-11)[J]. Pain, 2019, 160(1): 19-27. |
2 | Scholz J, Finnerup NB, Attal N, et al. The IASP classification of chronic pain for ICD-11: chronic neuropathic pain[J]. Pain, 2019, 160(1): 53-59. |
3 | Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment[J]. Physiol Rev, 2021, 101(1): 259-301. |
4 | Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain[J]. Nat Rev Dis Primers, 2017, 3: 17002. |
5 | Alles SRA, Smith PA. Etiology and pharmacology of neuropathic pain[J]. Pharmacol Rev, 2018, 70(2): 315-347. |
6 | Yam MF, Loh YC, Tan CS, et al. General pathways of pain sensation and the major neurotransmitters involved in pain regulation[J]. Int J Mol Sci, 2018, 19(8): 2164. |
7 | Cohen SP, Mao JR. Neuropathic pain: mechanisms and their clinical implications[J]. BMJ, 2014, 348: f7656. |
8 | Crawford LK, Caterina MJ. Functional anatomy of the sensory nervous system: updates from the neuroscience bench[J]. Toxicol Pathol, 2020, 48(1): 174-189. |
9 | Cui CX, Liu HY, Yue N, et al. Research progress on the mechanism of chronic neuropathic pain[J]. IBRO Neurosci Rep, 2023, 14: 80-85. |
10 | Miller KE, Hoffman EM, Sutharshan M, et al. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms[J]. Pharmacol Ther, 2011, 130(3): 283-309. |
11 | Levinson SR, Luo SJ, Henry MA. The role of so-dium channels in chronic pain[J]. Muscle Nerve, 2012, 46(2): 155-165. |
12 | Mickle AD, Shepherd AJ, Mohapatra DP. Sensory TRP channels: the key transducers of nociception and pain[J]. Prog Mol Biol Transl Sci, 2015, 131: 73-118. |
13 | Liu YN, Wang KW. Exploiting the diversity of ion channels: modulation of ion channels for therapeutic indications[J]. Handb Exp Pharmacol, 2019, 260: 187-205. |
14 | Cheng T, Xu ZL, Ma XQ. The role of astrocytes in neuropathic pain[J]. Front Mol Neurosci, 2022, 15: 1007889. |
15 | Liu F, Zhang YY, Song N, et al. GABAB receptor activation attenuates inflammatory orofacial pain by modulating interleukin-1β in satellite glial cells: role of NF‑κB and MAPK signaling pathways[J]. Brain Res Bull, 2019, 149: 240-250. |
16 | Zhang YY, Song N, Liu F, et al. Activation of mitogen-activated protein kinases in satellite glial cells of the trigeminal ganglion contributes to substance P-mediated inflammatory pain[J]. Int J Oral Sci, 2019, 11(3): 24. |
17 | Zhang YY, Song N, Liu F, et al. Activation of the RAS/B-RAF-MEK-ERK pathway in satellite glial cells contributes to substance p-mediated orofacial pain[J]. Eur J Neurosci, 2020, 51(11): 2205-2218. |
18 | Tatemoto K, Rökaeus A, Jörnvall H, et al. Galanin-a novel biologically active peptide from porcine intestine[J]. FEBS Lett, 1983, 164(1): 124-128. |
19 | Ch’ng JL, Christofides ND, Anand P, et al. Distribution of galanin immunoreactivity in the central nervous system and the responses of galanin-contai-ning neuronal pathways to injury[J]. Neuroscience, 1985, 16(2): 343-354. |
20 | Liu F, Yajima T, Wang M, et al. Effects of trigeminal nerve injury on the expression of galanin and its receptors in the rat trigeminal ganglion[J]. Neuropeptides, 2020, 84: 102098. |
21 | Hulse R, Wynick D, Donaldson LF. Characterization of a novel neuropathic pain model in mice[J]. Neuroreport, 2008, 19(8): 825-829. |
22 | Kerr BJ, Gupta Y, Pope R, et al. Endogenous galanin potentiates spinal nociceptive processing fo-llowing inflammation[J]. Pain, 2001, 93(3): 267-277. |
23 | Pope RJ, Holmes FE, Kerr NC, et al. Characterisation of the nociceptive phenotype of suppressible galanin overexpressing transgenic mice[J]. Mol Pain, 2010, 6: 67. |
24 | Fonseca-Rodrigues D, Almeida A, Pinto-Ribeiro F. A new gal in town: a systematic review of the role of galanin and its receptors in experimental pain[J]. Cells, 2022, 11(5): 839. |
25 | Šípková J, Kramáriková I, Hynie S, et al. The galanin and galanin receptor subtypes, its regulatory role in the biological and pathological functions[J]. Physiol Res, 2017, 66(5): 729-740. |
26 | Constantin S, Wray S. Galanin activates G protein gated inwardly rectifying potassium channels and suppresses kisspeptin-10 activation of GnRH neurons[J]. Endocrinology, 2016, 157(8): 3197-3212. |
27 | Xu SL, Li J, Zhang JJ, et al. Antinociceptive effects of galanin in the nucleus accumbens of rats[J]. Neurosci Lett, 2012, 520(1): 43-46. |
28 | Chen SH, Lue JH, Hsiao YJ, et al. Elevated galanin receptor type 2 primarily contributes to mechanical hypersensitivity after median nerve injury[J]. PLoS One, 2018, 13(6): e0199512. |
29 | Hulse RP, Donaldson LF, Wynick D. Differential roles of galanin on mechanical and cooling respon-ses at the primary afferent nociceptor[J]. Mol Pain, 2012, 8: 41. |
30 | Alier KA, Chen YS, Sollenberg UE, et al. Selective stimulation of GalR1 and GalR2 in rat substantia gelatinosa reveals a cellular basis for the anti- and pro-nociceptive actions of galanin[J]. Pain, 2008, 137(1): 138-146. |
31 | Li MN, Zhang XM, Li CY, et al. Galanin receptor 2 is involved in galanin-induced analgesic effect by activating PKC and CaMKⅡ in the nucleus accumbens of inflammatory pain rats[J]. Front Neurosci, 2020, 14: 593331. |
32 | Narváez M, Millón C, Borroto-Escuela D, et al. Galanin receptor 2-neuropeptide Y Y1 receptor interactions in the amygdala lead to increased anxiolytic actions[J]. Brain Struct Funct, 2015, 220(4): 2289-2301. |
33 | Yu M, Fang PH, Wang H, et al. Beneficial effects of galanin system on diabetic peripheral neuropathic pain and its complications[J]. Peptides, 2020, 134: 170404. |
34 | Botz B, Kemény Á, Brunner SM, et al. Lack of galanin 3 receptor aggravates murine autoimmune arthritis[J]. J Mol Neurosci, 2016, 59(2): 260-269. |
35 | Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products[J]. Nature, 1982, 298(5871): 240-244. |
36 | Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology[J]. Physiol Rev, 2014, 94(4): 1099-1142. |
37 | Kimura S, Sakuma Y, Suzuki M, et al. Evaluation of pain behavior and calcitonin gene-related peptide immunoreactive sensory nerve fibers in the spinal dorsal horn after sciatic nerve compression and application of nucleus pulposus in rats[J]. Spine, 2014, 39(6): 455-462. |
38 | Nitzan-Luques A, Minert A, Devor M, et al. Dynamic genotype-selective “phenotypic switching” of CGRP expression contributes to differential neuropathic pain phenotype[J]. Exp Neurol, 2013, 250: 194-204. |
39 | Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine[J]. Pain, 2017, 158(4): 543-559. |
40 | Bernstein C, Burstein R. Sensitization of the trige-minovascular pathway: perspective and implications to migraine pathophysiology[J]. J Clin Neurol, 2012, 8(2): 89-99. |
41 | Bonura A, Brunelli N, Marcosano M, et al. Calcitonin gene-related peptide systemic effects: embra-cing the complexity of its biological roles-a narrative review[J]. Int J Mol Sci, 2023, 24(18): 13979. |
42 | Marvizón JC, Pérez OA, Song B, et al. Calcitonin receptor-like receptor and receptor activity modi-fying protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing o-pioids and adrenergic alpha2C receptors[J]. Neuros-cience, 2007, 148(1): 250-265. |
43 | Labastida-Ramírez A, Caronna E, Gollion C, et al. Mode and site of action of therapies targeting CGRP signaling[J]. J Headache Pain, 2023, 24(1): 125. |
44 | Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology[J]. J Neurosci, 2015, 35(17): 6619-6629. |
45 | Rogoz K, Andersen HH, Kullander K, et al. Glutamate, substance P, and calcitonin gene-related peptide cooperate in inflammation-induced heat hyperal-gesia[J]. Mol Pharmacol, 2014, 85(2): 322-334. |
46 | Rogoz K, Andersen HH, Lagerström MC, et al. Multimodal use of calcitonin gene-related peptide and substance P in itch and acute pain uncovered by the elimination of vesicular glutamate transporter 2 from transient receptor potential cation channel subfamily V member 1 neurons[J]. J Neurosci, 2014, 34(42): 14055-14068. |
47 | Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide[J]. Proc Natl Acad Sci U S A, 1982, 79(18): 5485-5489. |
48 | Magnussen C, Hung SP, Ribeiro-da-Silva A. Novel expression pattern of neuropeptide Y immunoreactivity in the peripheral nervous system in a rat mo-del of neuropathic pain[J]. Mol Pain, 2015, 11: 31. |
49 | Diaz-delCastillo M, Woldbye DPD, Heegaard AM. Neuropeptide Y and its involvement in chronic pain[J]. Neuroscience, 2018, 387: 162-169. |
50 | Smith PA, Moran TD, Abdulla F, et al. Spinal mecha-nisms of NPY analgesia[J]. Peptides, 2007, 28(2): 464-474. |
51 | Zhang X, Shi T, Holmberg K, et al. Expression and regulation of the neuropeptide Y Y2 receptor in sensory and autonomic ganglia[J]. Proc Natl Acad Sci U S A, 1997, 94(2): 729-734. |
52 | Naveilhan P, Hassani H, Lucas G, et al. Reduced antinociception and plasma extravasation in mice la-cking a neuropeptide Y receptor[J]. Nature, 2001, 409(6819): 513-517. |
53 | Yan WH, Liu WC, Wu JL, et al. Neuropeptide Y in the amygdala contributes to neuropathic pain-like behaviors in rats via the neuropeptide Y receptor type 2/mitogen-activated protein kinase axis[J]. Bio-engineered, 2022, 13(4): 8101-8114. |
54 | Acton D, Ren XY, di Costanzo S, et al. Spinal neuropeptide Y1 receptor-expressing neurons form an essential excitatory pathway for mechanical itch[J]. Cell Rep, 2019, 28(3): 625-639.e6. |
55 | Nelson TS, Taylor BK. Targeting spinal neuropeptide Y1 receptor-expressing interneurons to alleviate chronic pain and itch[J]. Prog Neurobiol, 2021, 196: 101894. |
56 | Nelson TS, Sinha GP, Santos DFS, et al. Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain[J]. Proc Natl Acad Sci U S A, 2022, 119(46): e2204515119. |
57 | Eckstein M, Almeida de Minas AC, Scheele D, et al. Oxytocin for learning calm and safety[J]. Int J Psychophysiol, 2019, 136: 5-14. |
58 | Tzabazis A, Mechanic J, Miller J, et al. Oxytocin receptor: expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders[J]. Cephalalgia, 2016, 36(10): 943-950. |
59 | Li YX, Li JH, Guo Y, et al. Oxytocin inhibits hindpaw hyperalgesia induced by orofacial inflammation combined with stress[J]. Mol Pain, 2022, 18: 17448069221089591. |
60 | Kemenesi-Gedei PB, Csabafi KA, Kis G. Inflammatory orofacial pain activates peptidergic neurons and upregulates the oxytocin receptor expression in trigeminal ganglion[J]. Biomedicines, 2023, 11(9): 2419. |
61 | Gong L, Gao F, Li J, et al. Oxytocin-induced membrane hyperpolarization in pain-sensitive dorsal root ganglia neurons mediated by Ca2+/nNOS/NO/KATP pathway[J]. Neuroscience, 2015, 289: 417-428. |
62 | Kumamoto E. Cellular mechanisms for antinociception produced by oxytocin and orexins in the rat spinal lamina Ⅱ-comparison with those of other endo-genous pain modulators[J]. Pharmaceuticals (Basel), 2019, 12(3): 136. |
63 | Nersesyan Y, Demirkhanyan L, Cabezas-Bratesco D, et al. Oxytocin modulates nociception as an agonist of pain-sensing TRPV1[J]. Cell Rep, 2017, 21(6): 1681-1691. |
64 | Yang LN, Chen K, Yin XP, et al. The comprehensive neural mechanism of oxytocin in analgesia[J]. Curr Neuropharmacol, 2022, 20(1): 147-157. |
65 | Thakur P, Shrivastava R, Shrivastava VK. Effects of exogenous oxytocin and atosiban antagonist on GABA in different region of brain[J]. IBRO Rep, 2019, 6: 185-189. |
66 | Pigg M, Nixdorf DR, Law AS, et al. New international classification of orofacial pain: what is in it for endodontists[J]. J Endod, 2021, 47(3): 345-357. |
67 | Bonomini F, Favero G, Castrezzati S, et al. Role of neurotrophins in orofacial pain modulation: a review of the latest discoveries[J]. Int J Mol Sci, 2023, 24(15): 12438. |
68 | Bista P, Imlach WL. Pathological mechanisms and therapeutic targets for trigeminal neuropathic pain[J]. Medicines (Basel), 2019, 6(3): 91. |
69 | Messlinger K, Russo AF. Current understanding of trigeminal ganglion structure and function in hea-dache[J]. Cephalalgia, 2019, 39(13): 1661-1674. |
70 | Nagakura Y, Nagaoka S, Kurose T. Potential mole-cular targets for treating neuropathic orofacial pain based on current findings in animal models[J]. Int J Mol Sci, 2021, 22(12): 6406. |
71 | Messlinger K, Balcziak LK, Russo AF. Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators[J]. J Neural Transm, 2020, 127(4): 431-444. |
72 | Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond[J]. Physiol Rev, 2023, 103(2): 1565-1644. |
73 | Haanes KA, Labastida-Ramírez A, Blixt FW, et al. Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models[J]. Cephalalgia, 2019, 39(11): 1421-1434. |
74 | Starnowska-Sokół J, Przewłocka B. Multifunctional opioid-derived hybrids in neuropathic pain: preclinical evidence, ideas and challenges[J]. Molecules, 2020, 25(23): 5520. |
75 | Szok D, Tajti J, Nyári A, et al. Therapeutic approaches for peripheral and central neuropathic pain[J]. Behav Neurol, 2019, 2019: 8685954. |
76 | Bannister K, Sachau J, Baron R, et al. Neuropathic pain: mechanism-based therapeutics[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 257-274. |
77 | Tajti J, Szok D, Csáti A, et al. Exploring novel therapeutic targets in the common pathogenic factors in migraine and neuropathic pain[J]. Int J Mol Sci, 2023, 24(4): 4114. |
78 | Krishnaswamy R, Malik BH, Khan S, et al. Anti-CGRP monoclonal antibodies: breakthrough in migraine therapeutics[J]. Prog Neurol Psychiatry, 2019, 23(3): 26-33. |
79 | Kang SA, Govindarajan R. Anti-calcitonin gene-related peptide monoclonal antibodies for neuropathic pain in patients with migraine headache[J]. Muscle Nerve, 2021, 63(4): 563-567. |
80 | Harding SD, Armstrong JF, Faccenda E, et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2024[J]. Nucleic Acids Res, 2024, 52(D1): D1438-D1449. |
81 | Rich K, Rehman S, Jerman J, et al. Investigating the potential of GalR2 as a drug target for neuropathic pain[J]. Neuropeptides, 2023, 98: 102311. |
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