臨床研究指出當患者曝露於反覆及慢性的心理和生理壓力時會增加其對疼痛的
感受，然而在臨床前研究也發現各種形式的壓力都會使冰醋酸誘導的扭體反應明顯的
增加。已有研究提出背根神經節中的瞬態感受器陽離子電壓通道 (Transient receptor
potential vanilloid 1, TRPV1）涉及疼痛的處理，然而當瞬態感受器陽離子電壓通道缺
失時可能會抑制內臟的傷害感受和壓力反應。當小鼠的瞬態感受器陽離子電壓通道基
因缺失時會表現出對各種形式的壓力反應降低。而社會緩衝 (social buffering) 似乎減
少了冰醋酸對內臟有害刺激的疼痛處理。我們實驗室也進一步發現心理社會壓力的預
曝露可能透過上調伏隔核（Nucleus accumbens）中的瞬態感受器陽離子電壓通道表達
來增進內臟疼痛的程度。 有趣的是，也發現作為社交緩衝的小組測試可以防止此壓
力預曝露所引起的內臟疼痛程度增加，並且可使內側隔核（Medial septal nucleus）中
與冰醋酸注射相關的 c-Fos 蛋白表達顯著下降。因此，本研究將探討 1）阻斷伏隔核
中瞬態感受器陽離子電壓通道細胞內信號傳導是否可以避免壓力曝露的小鼠產生扭
體反應增加的情形、以及 2）使用藥理學和化學遺傳學方法增進內側隔核γ-氨基丁酸
神經元( GABAergic neuron）的活性以模仿社會緩衝效果來對抗壓力曝露所引發的疼
痛加劇和 3）從而防止伏隔核中壓力前曝露引起的瞬態感受器陽離子電壓通道之上調
現象。藥理學方法利用選擇性的瞬態感受器陽離子電壓通道拮抗劑 SB366791 於伏隔
核給藥以減少瞬態感受器陽離子電壓通道的信號傳導，以及內側隔核 bicuculline （一
種 GABAA 接受器拮抗劑）輸注以抑制γ-氨基丁酸神經元的活性。化學傳學方法則
在內側隔核給予 AAV-mDlx-Cre 和 AAV-hSyn-DIO-hM3D（Gq）-mCherry 混合病毒，並腹腔注射 C21 以增強該神經核內部γ-氨基丁酸神經元活性，反之給予 AAV-mDlxCre 和 AAV-hSyn-DIO-hM4D（Gi）-mCherry 混合病毒，並腹腔注射 C21 以抑制其γ-氨基丁酸神經元活性。研究結果顯示，雙側伏隔核 SB366791 輸注可防止壓力預曝露引起冰醋酸誘導的扭體反應增加，但不影響扭體反應本身的閾值。而內側隔核
bicuculline 輸注會消除社會緩衝造成的扭體反應減少之效果。相反的接受內側隔核II
AAV-mDlx-Cre，AAV-hSyn-DIO-hM3D（Gq）-mCherry 病毒和 C21 腹腔注射的小鼠表現出類似社會緩衝的作用，並且這種作用降低了瞬態感受器陽離子電壓通道和蛋白激
酶 C 的 ε-型，而不是蛋白激酶 C 的 α-型，在內側隔核中的表達。此外接受內側隔核
AAV-mDlx-Cre，AAV-hSyn-DIO-hM4D（Gi）-mCherry 病毒和 C21 腹腔注射的小鼠表現出類似壓力前曝露的作用，並且這種作用增加了瞬態感受器陽離子電壓通道和蛋白
激酶 C 的 ε-型，而不是蛋白激酶 C 的 α-型，在內側隔核中的表達。總結實驗結果之
結論為 1）伏隔核中瞬態感受器陽離子電壓通道的過度表達與壓力預曝露所導致冰醋
酸誘導的扭體反應加劇有關，2）小組測試的效果似乎與內側隔核的γ-氨基丁酸神經
元有關，又 3）內側隔核的γ-氨基丁酸神經元與內臟疼痛的調節有關。

Clinical studies have pointed out that repeated or chronic exposure to physical or
psychological stressors may enhance chronic pain magnitudes in patients. Likewise, various forms of stress are found to produce significant escalation in acetic acid-induced writhing responses in preclinical studies. Transient receptor potential vanilloid 1 (TRPV1) receptor in dorsal root ganglion neurons has been proposed involving in pain processing. And deletion of TRPV1 receptor may dampen visceral nociception and stress responses. When the Trpv1
gene is knocked out, mice demonstrate reduced responses to various forms of stressor. Social support seems to diminish pain processing following noxious visceral stimulation with acetic acid. Moreover, we have lately found that psychosocial stress pre-exposure increases the magnitude of visceral pain very likely by upregulating TRPV1 receptor expression in nucleus accumbens (NAc). Interestingly, group test, serving as social buffering, has been found to prevent such stress pre-exposure-produced escalation in visceral pain magnitudes
and to render evident decline in acid injection-associated c-Fos expression in medial septum(MS). Thus, this study was undertaken 1)to test a hypothesis whether blocking NAc TRPV1 intracellular signaling cascade may prevent the stress pre-exposure-produced escalation in acid-induced writhing responses in social defeat stress-pre-exposed mice and 2)to assess whether strengthening MS GABAergic neuronal activity by exploiting pharmacological and chemogenetic methods may mimic the social buffering-like effect against the stress preexposure-primed pain escalation effect and 3)thus to prevent stress pre-exposure-caused TRPV1 upregulation in NAc. Intra-accumbal SB366791, a selective TRPV1 antagonist, administration was used to diminish TRPV1 signaling cascade, while intra-medial septal bicuculline, a GABAA receptor antagonist, infusion was for dampening GABAergic activity. Combined intra-medial septal AAV-mDlx-Cre and AAV-hSyn-DIO-hM3D(Gq)-mCherry treatment followed by systemic Compound 21 (C21) injection was used to enhance local IV GABAergic neuronal activity. In contrast, combined intra-medial septal AAV-mDlx-Cre and
AAV-hSyn-DIO-hM4D(Gi)-mCherry treatment followed by systemic Compound 21 (C21) injection was used to diminish local GABAergic neuronal activity. The results have indicated that bilateral intra-accumbal SB366791 infusions may prevent the stress pre-exposureproduced escalation in acid-induced writhing responses, while do not affect the threshold of the writhing response per se. Moreover, intra-medial septum infusion with bicuculline may abolish the group-mediated writhing-reducing effects. In contrast, mice receiving intramedial septal AAV-mDlx-Cre, AAV-hSyn-DIO-hM3D(Gq)-mCherry and systemic C21 treatment but sparing the group test display social buffering-like effect in this regard and this effect decreased TRPV1 and PKC epsilon, not alpha, expression in MS. In addition, mice
receiving intra-medial septal AAV-mDlx-Cre, AAV-hSyn-DIO-hM4D(Gi)-mCherry and systemic C21 treatment display defeat stress-like effect in this regard and this effect increased TRPV1 and PKC epsilon, not alpha, expression in MS. These results, in together, prompt me to draw the following conclusions that 1) accumbal TRPV1 over-expression is involved in the stress pre-exposure-primed escalation in acid-induced writhing responses; and 2) group test effects seem to associate with the GABAergic tone in medial septum; and 3) medial septal GABAergic neuron is associated with the regulation of visceral pain.

1. Anthony R. H. & Qasim A. (2003). Central nervous system processing of human visceral pain in health and disease. News in Physiological Sciences, 18, 109–114.
2. Birder, L. A., Nakamura, Y., Kiss, S., Nealen, M. L., Barrick, S., Kanai, A. J., Wang, E.,
Ruiz, G., de Groat, W.C., Apodaca, G., Watkins S., & Caterina, M. J. (2002). Altered
urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature
Neuroscience, 5(9), 856–860.
3. Brown, J. L., Sheffield, D., Leary, M. R., & Robinson, M. E. (2003). Social support and experimental pain. Psychosomatic Medicine, 65(2), 276–283.
4. Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., Koltzenburg, M., Basbaum, A. I., & Julius, D., (2000). Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288(5464), 306–313.
5. Caterina, M. J., & Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annual Review of Neuroscience, 24(1), 487–517.
6. Cervero, F. (2009). Visceral versus Somatic Pain: Similarities and Differences. Digestive Diseases, 27(1), 3–10.
7. Coe, C. L., Mendoza, S. P., Smotherman, W. P., & Levine, S. (1978). Mother-infant
attachment in the squirrel monkey: Adrenal response to separation. Behavioral Biology, 22(2), 256–263.
8. Crettaz, B., Marziniak, M., Willeke, P., Young, P., Hellhammer, D., Stumpf, A., &
Burgmer, M. (2013). Stress-induced allodynia – evidence of increased pain sensitivity in healthy humans and patients with chronic pain after experimentally induced psychosocial stress. PLoS ONE, 8(8), e69460.
9. Morrison, B. J., & Hill, W. F. (1967). Socially facilitated reduction of the fear response in rats raised in groups or in isolation. Journal of Comparative and Physiological Psychology, 63(1), 71–76..
10. Deng, K., Yang, L., Xie, J., Tang, H., Wu, G.-S., & Luo, H.-R. (2019). Whole-brain
mapping of projection from mice lateral septal nucleus. Biology Open, bio.043554.
11. Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: Potential therapeutic targets. Science, 338(6103), 68–72.
12. Enna, S. J., & McCarson, K. E. (2006). The role of GABA in the mediation and
perception of pain. Advances in Pharmacology, 1–27.
13. Faustino, A. I., Tacão-Monteiro, A., & Oliveira, R. F. (2017). Mechanisms of social
buffering of fear in zebrafish. Scientific Reports, 7(1).
14. Story, G. (2006). The Emerging Role of TRP Channels in Mechanisms of Temperature and Pain Sensation. Current Neuropharmacology, 4(3), 183–196.
15. Golden, S. A., Covington, H. E., Berton, O., & Russo, S. J. (2015). Corrigendum: A
standardized protocol for repeated social defeat stress in mice. Nature Protocols, 10(4), 644–644.
16. Grundy, L., Erickson, A., & Brierley, S. M. (2018). Visceral Pain. Annual Review of
Physiology, 81(1).
17. Hennessy, M. B., Zate, R., & Maken, D. S. (2008). Social buffering of the cortisol
response of adult female guinea pigs. Physiology & Behavior, 93(4-5), 883–888.
18. Huang Y. H., et al. Social defeat /psychosocial stress pre-exposure produces increases in the acetic acid-induced writhing possibly via upregulation of TRPV1 receptor in the nucleus accumbens (2019).
19. Huzard, D., Mumby, D. G., Sandi, C., Poirier, G. L., & van der Kooij, M. A. (2015). The effects of extrinsic stress on somatic markers and behavior are dependent on animal housing conditions. Physiology & Behavior, 151, 238–245.
20. Jardín, I., López, J. J., Diez, R., Sánchez-Collado, J., Cantonero, C., Albarrán, L., 19
Woodard, E., Redondo C., Salido, M., Smani, T., & Rosado, J. A. (2017). TRPs in pain
sensation. Frontiers in Physiology, 8.
21. Jennings, E. M., Okine, B. N., Roche, M., & Finn, D. P. (2014). Stress-induced
hyperalgesia. Progress in Neurobiology, 121, 1–18.
22. Jiang, Y.-Y., Shao, S., Zhang, Y., Zheng, J., Chen, X., Cui, S., , Liua, F.-Y., Wan, Y., &
Yi, M. (2018). Neural pathways in medial septal cholinergic modulation of chronic pain. PAIN, 159(8), 1550–1561.
23. Jones, R. C. W. (2005). The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. Journal of Neuroscience, 25(47), 10981–10989.
24. Jurik, A., Ressle, A., Schmid, R. M., Wotjak, C. T., & Thoeringer, C. K. (2014).
Supraspinal TRPV1 modulates the emotional expression of abdominal pain. Pain,
155(10), 2153–2160.
25. Kamarudin, N., Hisamuddin, N., Ong, H., Ahmad Azmi, A., Leong, S., Abas, F., Roslan Sulaiman, M., & Shaik Mossadeq, W. (2018). Analgesic effect of 5-(3,4-
Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one in
experimental animal models of nociception. Molecules, 23(9), 2099.
26. Kikusui, T., Winslow, J. T., & Mori, Y. (2006). Social buffering: relief from stress and anxiety. Philosophical Transactions of the Royal Society B: Biological Sciences,
361(1476), 2215–2228.
27. Levine, S., Coe, C., Smotherman, W., & Kaplan, J. (1978). Prolonged cortisol elevation in the infant squirrel monkey after reunion with mother. Physiology & Behavior, 20(1), 7–10.
28. Marrone, M. C., Morabito, A., Giustizieri, M., Chiurchiù, V., Leuti, A., Mattioli, M.,
Marinelli, S., Riganti, L., Lombard,i M., Murana, E., Totaro, A., Piomelli, D., Ragozzino, D., Oddi S., Maccarrone, M., Verderio, C., & Marinelli, S. (2017). TRPV1 channels are
critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nature Communications, 8, 15292.
29. Moloney, R. D., O`Mahony, S. M., Dinan, T. G., & Cryan, J. F. (2015). Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Frontiers in Psychiatry, 6.
30. Berton, O., McClung, C. A., Dileone, R. J., Krishnan, V., Renthal, W., Russo, S. J.,
Graham, D., Tsankova, N. M., Bolanos ,C. A., Rios, M., Monteggia, L. M., Self, D. W.,
& Nestler, E. J. (2006). Essential role of BDNF in the mesolimbic dopamine pathway
in social defeat stress. Science, 311(5762), 864–868.
31. Pagliusi Jr, M. O. F., Bonet, I. J. M., Dias, E. V., Vieira, A. S., Tambeli, C. H., Parada, C. A., & Sartori, C. R. (2018). Social defeat stress induces hyperalgesia and increases
truncated BDNF isoforms in the nucleus accumbens regardless of the depressive-like behavior induction in mice. European Journal of Neuroscience, 48(1), 1635–1646.
32. Pitcher, M. H., Gonzalez-Cano, R., Vincent, K., Lehmann, M., Cobos, E. J., Coderre, T. J., Coderre, J. M., & Cervero, F. (2017). Mild social stress in mice produces opioidmediated analgesia in visceral but not somatic pain states. The Journal of Pain, 18(6), 716–725.
33. Mandadi, S., Armati, P. J., & Roufogalis, B. D. (2016). Protein kinase C modulation of thermo-sensitive transient receptor potential channels: Implications for pain signaling. The Journal of Natural Science, Biology and Medicine, 2(1): 13–25.
34. Takahashi, A., Chung, J.-R., Zhang, S., Zhang, H., Grossman, Y., Aleyasin, H., Flanigan, M. E., Pfau1, M. L., Menard, C., Dumitriu, D., Hodes, G. E., McEwen, B. S., Nestler, E. J., Han. M.-H., & Russo, S. J. (2017). Establishment of a repeated social defeat stress model in female mice. Scientific Reports, 7(1).21
35. Thorsteinsson, E. B., James, J. E., & Gregg, M. E. (1998). Effects of video-relayed social support on hemodynamic reactivity and salivary cortisol during laboratory-based behavioral challenge. Health Psychology, 17(5), 436–444.
36. Tsanov, M. (2017). Differential and complementary roles of medial and lateral septum in the orchestration of limbic oscillations and signal integration. European Journal of Neuroscience, 48(8):2783-2794.
37. Tzeng, W.-Y., Chuang, J.-Y., Lin, L.-C., Cherng, C. G., Lin, K.-Y., Chen, L.-H., Su, C.-
C., & Yu, L. (2013). Companions reverse stressor-induced decreases in neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in dentate gyrus. Psychoneuroendocrinology, 38(3), 425–437.
38. Tzeng, W.-Y., Chen, L.-H., Cherng, C. G., Tsai, Y.-N., & Yu, L. (2014). Sex differences and the modulating effects of gonadal hormones on basal and the stressor-decreased newly proliferative cells and neuroblasts in dentate gyrus. Psychoneuroendocrinology,
42, 24–37.
39. Tzeng, W.-Y., Cherng, C.-F. G., Wang, S.-W., & Yu, L. (2016). Familiar companions
diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens. Behavioural Brain Research, 306, 146–153.
40. Tzeng, W.-Y., Cherng, C.-F. G., Yu, L., & Wang, C.-Y. (2017). Basolateral amygdalar D 2 receptor activation is required for the companions-exerted suppressive effect on the cocaine conditioning. Neurobiology of Learning and Memory, 137, 48–55.
41. Tzeng, W.-Y., Wu, H.-H., Wang, C.-Y., Chen, J.-C., Yu, L., & Cherng, C. G. (2017). Sex Differences in Stress and Group Housing Effects on the Number of Newly Proliferated Cells and Neuroblasts in Middle-Aged Dentate Gyrus. Frontiers in Behavioral Neuroscience, 10:249.
42. Tzeng, W.-Y., Su, C.-C., Sun L.-H., Cherng, C. G. & Yu, L. (2018). Synergistic effects of psychosocial stress and mild peripheral infection on inducing microglial activation in the hippocampal dentate gyrus and long-lasting deficits in hippocampus-related memory. Chinese Journal of Physiology, 61(2):106-117.
43. Wang, S. E., Ko, S. Y., Jo, S., Choi, M., Lee, S. H., Jo, H.-R., Seo, J. Y., Lee, S. H., Kim,
Y. S., Sung, J. J., & Son, H. (2017). TRPV1 regulates stress responses through HDAC2. Cell Reports, 19(2), 401–412.
44. Wang, Y., Gao, Y., Tian, Q., Deng, Q., Wang, Y., Zhou, T., Liu, Q., Mei, K., Wang, Y.,
Liu, H., Ma, R., Ding, Y., Rong, W., Cheng, J., Yao J., Xu T.-L., Zhu, M. X., & Li, Y.
(2018). TRPV1 SUMOylation regulates nociceptive signaling in models of
inflammatory pain. Nature Communications, 9(1).
45. Wang, Z., Ling, D., Wu, C., Han, J., & Zhao, Y. (2020). Baicalin prevents the up‐
regulation of TRPV1 in dorsal root ganglion and attenuates chronic neuropathic pain. Veterinary Medicine and Science. 6(4):1034-1040.
46. Will, M. J., Franzblau, E. B., & Kelley, A. E. (2003). Nucleus accumbens μ-opioids
regulate intake of a high-fat diet via activation of a distributed brain network. The
Journal of Neuroscience, 23(7), 2882–2888.
47. Xiao, X., Zhao, X.-T., Xu, L.-C., Yue, L.-P., Liu, F.-Y., Cai, J., Liao, F.-F., Kong, J.-G.,
Xing, G.-G., Yi, M., & Wan, Y. (2015). Shp-1 dephosphorylates TRPV1 in dorsal root
ganglion neurons and alleviates CFA-induced inflammatory pain in rats. PAIN, 156(4), 597–608.
48. Xiao, Y., Chen, X., Zhang, P.-A., Xu, Q., Zheng, H., & Xu, G.-Y. (2016). TRPV1-
mediated presynaptic transmission in basolateral amygdala contributes to visceral
hypersensitivity in adult rats with neonatal maternal deprivation. Scientific Reports, 6(1).
49. Zygmunt, P. M., Ermund, A., Movahed, P., Andersson, D. A., Simonsen, C., Jönsson, B. A. G., Blomgren, A., Birnir, B., Bevan, S., Eschalier, A., Mallet, C., Gomis, A., & 23Högestätt, E. D. (2013). Monoacylglycerols activate TRPV1 – a link between
phospholipase C and TRPV1. PLoS ONE, 8(12), e81618.