Molecular Pain | |
Optogenetic activation of brainstem serotonergic neurons induces persistent pain sensitization | |
Zhizhong Z Pan1  Yuan-Yuan Hou1  Wei Wang1  You-Qing Cai1  | |
[1] Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA | |
关键词: Pain; Rostral ventromedial medulla; Descending facilitation; Optogenetic; 5-HT; Serotonin; | |
Others : 1135559 DOI : 10.1186/1744-8069-10-70 |
|
received in 2014-04-16, accepted in 2014-06-18, 发布年份 2014 | |
【 摘 要 】
Background
The rostral ventromedial medulla (RVM) is a key brainstem structure that conveys powerful descending influence of the central pain-modulating system on spinal pain transmission and processing. Serotonergic (5-HT) neurons are a major component in the heterogeneous populations of RVM neurons and in the descending pathways from RVM. However, the descending influence of RVM 5-HT neurons on pain behaviors remains unclear.
Results
In this study using optogenetic stimulation in tryptophan hydroxylase 2 (TPH2)- Channelrhodopsin 2 (ChR2) transgenic mice, we determined the behavioral effects of selective activation of RVM 5-HT neurons on mechanical and thermal pain behaviors in vivo. We found that ChR2-EYFP-positive neurons strongly co-localized with TPH2-positive (5-HT) neurons in RVM. Optogenetic stimulation significantly increased c-fos expression in 5-HT cells in the RVM of TPH2-ChR2 mice, but not in wild type mice. Behaviorally, the optogenetic stimulation decreased both mechanical and thermal pain threshold in an intensity-dependent manner, with repeated stimulation producing sensitized pain behavior for up to two weeks.
Conclusions
These results suggest that selective activation of RVM 5-HT neurons exerts a predominant effect of pain facilitation under control conditions.
【 授权许可】
2014 Cai et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150310063118127.pdf | 1947KB | download | |
Figure 6. | 42KB | Image | download |
Figure 5. | 43KB | Image | download |
Figure 4. | 36KB | Image | download |
Figure 3. | 84KB | Image | download |
Figure 2. | 203KB | Image | download |
Figure 1. | 211KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
【 参考文献 】
- [1]Basbaum AI, Bautista DM, Scherrer G, Julius D: Cellular and molecular mechanisms of pain. Cell 2009, 139:267-284.
- [2]Fields H: State-dependent opioid control of pain. Nat Rev Neurosci 2004, 5:565-575.
- [3]Millan MJ: Descending control of pain. Prog Neurobiol 2002, 66:355-474.
- [4]Fields HL, Heinricher MM, Mason P: Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991, 14:219-245.
- [5]Porreca F, Ossipov MH, Gebhart GF: Chronic pain and medullary descending facilitation. Trends Neurosci 2002, 25:319-325.
- [6]Gebhart GF: Descending modulation of pain. Neurosci Biobehav Rev 2004, 27:729-737.
- [7]Vanegas H, Schaible HG: Descending control of persistent pain: inhibitory or facilitatory? Brain Res Brain Res Rev 2004, 46:295-309.
- [8]Robinson DA, Calejesan AA, Wei F, Gebhart GF, Zhuo M: Endogenous facilitation: from molecular mechanisms to persistent pain. Curr Neurovasc Res 2004, 1:11-20.
- [9]Buhler AV, Choi J, Proudfit HK, Gebhart GF: Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the rostral ventromedial medulla is antinociceptive. Pain 2005, 114:285-294.
- [10]Calejesan AA, Ch’ang MH, Zhuo M: Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats. Brain Res 1998, 798:46-54.
- [11]Hammond DL, Yaksh TL: Antagonism of stimulation-produced antinociception by intrathecal administration of methysergide or phentolamine. Brain Res 1984, 298:329-337.
- [12]Wei F, Dubner R, Ren K: Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation. Pain 1999, 80:127-141.
- [13]Zhao ZQ, Chiechio S, Sun YG, Zhang KH, Zhao CS, Scott M, Johnson RL, Deneris ES, Renner KJ, Gereau RW, Chen ZF: Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. J Neurosci 2007, 27:6045-6053.
- [14]Kim YS, Chu Y, Han L, Li M, Li Z, Lavinka PC, Sun S, Tang Z, Park K, Caterina MJ, Ren K, Dubner R, Wei F, Dong X: Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain. Neuron 2014, 81:873-887.
- [15]Wei F, Dubner R, Zou S, Ren K, Bai G, Wei D, Guo W: Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci 2010, 30:8624-8636.
- [16]Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K: Optogenetics in neural systems. Neuron 2011, 71:9-34.
- [17]Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S: Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012, 484:381-385.
- [18]Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K: Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 2011, 471:358-362.
- [19]Tye KM, Deisseroth K: Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci 2012, 13:251-266.
- [20]Ji G, Neugebauer V: Modulation of medial prefrontal cortical activity using in vivo recordings and optogenetics. Mol Brain 2012, 5:36. BioMed Central Full Text
- [21]Daou I, Tuttle AH, Longo G, Wieskopf JS, Bonin RP, Ase AR, Wood JN, De Koninck Y, Ribeiro-da-Silva A, Mogil JS, Seguela P: Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci 2013, 33:18631-18640.
- [22]Crock LW, Kolber BJ, Morgan CD, Sadler KE, Vogt SK, Bruchas MR, Gereau RW: Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci 2012, 32:14217-14226.
- [23]Ito H, Yanase M, Yamashita A, Kitabatake C, Hamada A, Suhara Y, Narita M, Ikegami D, Sakai H, Yamazaki M: Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons. Mol Brain 2013, 6:59. BioMed Central Full Text
- [24]Zhao S, Ting JT, Atallah HE, Qiu L, Tan J, Gloss B, Augustine GJ, Deisseroth K, Luo M, Graybiel AM, Feng G: Cell type-specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function. Nat Methods 2011, 8:745-752.
- [25]Braz JM, Basbaum AI: Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits. J Comp Neurol 2008, 507:1990-2003.
- [26]Braz JM, Enquist LW, Basbaum AI: Inputs to serotonergic neurons revealed by conditional viral transneuronal tracing. J Comp Neurol 2009, 514:145-160.
- [27]Rahman W, Bauer CS, Bannister K, Vonsy JL, Dolphin AC, Dickenson AH: Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain. Mol Pain 2009, 5:45. BioMed Central Full Text
- [28]Okubo M, Castro A, Guo W, Zou S, Ren K, Wei F, Keller A, Dubner R: Transition to persistent orofacial pain after nerve injury involves supraspinal serotonin mechanisms. J Neurosci 2013, 33:5152-5161.
- [29]Aimone LD, Gebhart GF: Stimulation-produced spinal inhibition from the midbrain in the rat is mediated by an excitatory amino acid neurotransmitter in the medial medulla. J Neurosci 1986, 6:1803-1813.
- [30]Inase M, Nakahama H, Otsuki T, Fang JZ: Analgesic effects of serotonin microinjection into nucleus raphe magnus and nucleus raphe dorsalis evaluated by the monosodium urate (MSU) tonic pain model in the rat. Brain Res 1987, 426:205-211.
- [31]Llewelyn MB, Azami J, Roberts MH: Effects of 5-hydroxytryptamine applied into nucleus raphe magnus on nociceptive thresholds and neuronal firing rate. Brain Res 1983, 258:59-68.
- [32]Marinelli S, Vaughan CW, Schnell SA, Wessendorf MW, Christie MJ: Rostral ventromedial medulla neurons that project to the spinal cord express multiple opioid receptor phenotypes. J Neurosci 2002, 22:10847-10855.
- [33]Wang H, Wessendorf MW: Mu- and delta-opioid receptor mRNAs are expressed in spinally projecting serotonergic and nonserotonergic neurons of the rostral ventromedial medulla. J Comp Neurol 1999, 404:183-196.
- [34]Alhaider AA, Lei SZ, Wilcox GL: Spinal 5-HT3 receptor-mediated antinociception: possible release of GABA. J Neurosci 1991, 11:1881-1888.
- [35]Green GM, Scarth J, Dickenson A: An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT(3) receptors in the anaesthetized rat. Pain 2000, 89:81-88.
- [36]Gu M, Miyoshi K, Dubner R, Guo W, Zou S, Ren K, Noguchi K, Wei F: Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade. J Neurosci 2011, 31:12823-12836.
- [37]Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S: Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain 2007, 130:235-248.
- [38]Oatway MA, Chen Y, Weaver LC: The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury. Pain 2004, 110:259-268.
- [39]Paul D, Yao D, Zhu P, Minor LD, Garcia MM: 5-hydroxytryptamine3 (5-HT3) receptors mediate spinal 5-HT antinociception: an antisense approach. J Pharmacol Exp Ther 2001, 298:674-678.
- [40]Svensson CI, Tran TK, Fitzsimmons B, Yaksh TL, Hua XY: Descending serotonergic facilitation of spinal ERK activation and pain behavior. FEBS Lett 2006, 580:6629-6634.
- [41]Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L, Bonhaus DW, Stucky CL, Julius D, Basbaum AI: The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci 2002, 22:1010-1019.
- [42]Zhang L, Hammond DL: Cellular basis for opioid potentiation in the rostral ventromedial medulla of rats with persistent inflammatory nociception. Pain 2010, 149:107-116.
- [43]Kuner R: Central mechanisms of pathological pain. Nat Med 2010, 16:1258-1266.
- [44]Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53:55-63.
- [45]Cai YQ, Chen SR, Pan HL: Upregulation of nuclear factor of activated T-cells by nerve injury contributes to development of neuropathic pain. J Pharmacol Exp Ther 2013, 345:161-168.
- [46]Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32:77-88.