Abstract
Rationale
Nucleus cuneiformis (NC), a reticular nucleus of the midbrain, is a part of the descending pain modulatory system and therefore has an important role in pain perception.
Objectives
Considering the abundance of GABAA and cannabinoid receptors in the NC and also the bidirectional roles for GABA in controlling nociception, the present study examined the effects of bilateral intra-NC microinjection of different doses of the GABAA receptor agonist, muscimol, and the GABAA receptor antagonist, bicuculline, on pain modulation using formalin test. We also assessed interaction between canabinergic and GABAergic systems in the NC during this test.
Methods
Rats were exposed to intra-NC microinjection of bicuculline (50,100, and 200 ng/side) or muscimol (60, 120, and 240 ng/side) and then subjected to the formalin test. In another set of experiments, the effects of muscimol (60 ng/side) or bicuculline (50 ng/side) administration 5 min before a cannabinoid receptor agonist WIN 55,212-2 (5, 10, and 20 μg/side) microinjection into NC on the formalin test were evaluated.
Results
Microinjection of bicuculline and muscimol into the NC decreased and increased pain responses, respectively, in a dose-dependent manner during both phases of the test. Microinjection of WIN 55,212-2 into the NC significantly reduced pain responses in a dose-dependent manner. Microinjection of bicuculline or muscimol in combination with WIN 55,212-2 into the NC respectively potentiated and attenuated WIN 55,212-2–induced antinociception in the formalin test.
Conclusions
This study shows that GABA in the NC is involved in pain modulation and suggests the existence of a GABAA-mediated inhibitory system in the NC on pain control. Furthermore, it seems that the antinociceptive effect of WIN 55,212-2 in the formalin test is mediated partly by the activity of local GABAA receptors in the NC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abbott FV, Franklin KB, Westbrook RF (1995) The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain 60:91–102. https://doi.org/10.1016/0304-3959(94)00095-V
Bernard JF, Peschanski M, Besson JM (1989) Afferents and efferents of the rat cuneiformis nucleus: an anatomical study with reference to pain transmission. Brain Res 490:181–185. https://doi.org/10.1016/0006-8993(89)90449-6
Bloom AS, Dewey WL, Harris LS, Brosius KK (1977) 9-Nor-9betahydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine. J Pharmacol Exp Ther 200:263–270
Celotto L, Eroli F, Nistri A, Vilotti S (2019) Long-term application of cannabinoids leads to dissociation between changes in cAMP and modulation of GABAA receptors of mouse trigeminal sensory neurons. Neurochem Int 126:74–85. https://doi.org/10.1016/j.neuint.2019.01.007
Chiu CQ, Puente N, Grandes P, Castillo PE (2010) Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. J Neurosci 30:7236–7248. https://doi.org/10.1523/JNEUROSCI.0736-10.2010
Coderre TJ, Fundytus ME, McKenna JEC, Dalal S, Melzack R (1993) The formalin test: a validation of the weighted-scores method of behavioural pain rating. Pain 54:43–50. https://doi.org/10.1016/0304-3959(93)90098-a
Cohen K, Abraham W, Aviv W (2019) Modulatory effects of cannabinoids on brain neurotransmission. Eur J Neurosci 50:2322–2345. https://doi.org/10.1111/ejn.14407
da Motta PG, Veiga AP, Francischi JN, Tatsuo MA (2004) Evidence for participation of GABA(A) receptors in a rat model of secondary hyperalgesia. Eur J Pharmacol 483:233–239. https://doi.org/10.1016/j.ejphar.2003.10.015
Ebrahimzadeh M, Haghparast A (2011) Analgesic effects of cannabinoid receptor agonist WIN55, 212-2 in the nucleus cuneiformis in animal models of acute and inflammatory pain in rats. Brain Res 1420:19–28. https://doi.org/10.1016/j.brainres.2011.08.028
Elmes SJR, Winyard LA, Medhurst SJ, Clayton NM, Wilson AW, Kendall DA, Chapman V (2005) Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 118(3):327–335
Fang Q, Han ZL, Li N, Wang ZL, He N, Wang R (2012) Effects of neuropeptide FF system on CB1 and CB2 receptors mediated antinociception in mice. Neuropharmacol 62:855–864
Freitas RL, Salgado-Rohner CJ, Hallak JEC, de Souza Crippa JA, Coimbra NC (2013) Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor. Int J Neuropsychopharmacol 16:1781–1798. https://doi.org/10.1017/S1461145713000163
Gilbert AK, Franklin KB (2001) GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM) dose–response analysis of nociception and neurological deficits. Pain 90:25–36. https://doi.org/10.1016/s0304-3959(00)00383-3
Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG (2003) Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception. Brain Res 987:176–185. https://doi.org/10.1016/s0006-8993(03)03324-9
Haghparast A, Ahmad-Molaei L (2009) Effects of electrolytic lesion of dorsolateral periaqueductal gray on analgesic response of morphine microinjected into the nucleus cuneiformis in rat. Neurosci Lett 451:165–169. https://doi.org/10.1016/j.neulet.2008.12.058
Haghparast A, Soltani-Hekmat A, Khani A, Komaki A (2007) Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat. Neurosci Lett 427:44–49. https://doi.org/10.1016/j.neulet.2007.09.003
Hammond DL (2001) Role of spinal GABA in acute and persistent nociception. Reg Anesth Pain Med 26:551–557. https://doi.org/10.1053/rapm.2001.27835
Han ZL, Wang ZL, Li XH, Li N, Pan JX, Zheng T, Fang Q, Wang R (2015) Neuropeptide VF enhances cannabinoid agonist WIN55,212-2-induced antinociception in mice. Anesth Analg 121:1360–1368. https://doi.org/10.1213/ANE.0000000000000921
Hasanein P, Mirazi N, Javanmardi K (2008) GABAA receptors in the central nucleus of amygdala (CeA) affect on pain modulation. Brain Res 1241:36–41. https://doi.org/10.1016/j.brainres.2008.09.041
Hasanein P, Parviz M, Keshavarz M, Javanmardi K (2007) CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception. Clin Exp Pharmacol Physiol 34:439–449. https://doi.org/10.1111/j.1440-1681.2007.04592.x
Hasanein P, Sharifi M (2015) GABA (A) receptors in the central amygdala are involved in memory retention deficits induced by cannabinoids in rats. Pharmacol Biochem Behav 138:26–31. https://doi.org/10.1016/j.pbb.2015.09.010
Heinricher MM, Kaplan HJ (1991) GABA-mediated inhibition in rostral ventromedial medulla: role in nociceptive modulation in the lightly anesthetized rat. Pain 47:105–113. https://doi.org/10.1016/0304-3959(91)90017-r
Ibrahim MM, Rude ML, Stagg NJ, Mata HP, Lai J, Vanderah TW, Porreca F, Buckley NE, Makriyannis A, Malan TP Jr (2006) CB2 cannabinoid receptor mediation of antinociception. Pain 122:36–42
Iversen L (2003) Cannabis and the brain. Brain 126:1252–1270. https://doi.org/10.1093/brain/awg143
Jia H, Xie YF, Xiao DQ, Tang JS (2004) Involvement of GABAergic modulation of the nucleus submedius (Sm) morphine-induced antinociception. Pain 108:28–35. https://doi.org/10.1016/j.pain.2003.11.012
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380. https://doi.org/10.1152/physrev.00019.2008
Mahmoudi M, Zarrindast MR (2002) Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test. J Psychopharmacol 16:85–91. https://doi.org/10.1177/026988110201600108
Manning BH, Martin WJ, Meng ID (2003) The rodent amygdala contributes to the production of cannabinoid-induced antinociception. Neuroscience 120:1157–1170. https://doi.org/10.1016/s0306-4522(03)00356-7
Martin WJ, Coffin PO, Attias E, Balinsky M, Tsou K, Walker JM (1999) Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res 822:237–242. https://doi.org/10.1016/s0006-8993(98)01368-7
Martin WJ, Patrick SL, Coffin PO, Tsou K, Walker JM (1995) An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sci 56:2103–2109. https://doi.org/10.1016/0024-3205(95)00195-c
McDonald AJ, Mascagni F (2004) Parvalbumin-containing interneurons in the basolateral amygdale express high levels of the α1 subunit of the GABA (A) receptor. J Comp Neurol 473:137–146. https://doi.org/10.1002/cne.20101
McGowan MK, Hammond DL (1993) Antinociception produced by microinjection of l-glutamate into the ventromedial medulla of the rat: mediation by spinal GABA (A) receptors. Brain Res 620:86–96. https://doi.org/10.1016/0006-8993(93)90274-Q
Millan MJ (1999) The induction of pain: an integrative review. Prog Neurobiol 57:1–164. https://doi.org/10.1016/S0301-0082(98)00048-3
Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474. https://doi.org/10.1016/S0301-0082(02)00009-6
Moreau JL, Fields HL (1986) Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission. Brain Res 397:37–46. https://doi.org/10.1016/0006-8993(86)91367-3
Naderi N, Shafaghi B, Khodayar MJ, Zarindast MR (2005) Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat. Eur J Pharmacol 514:159–164. https://doi.org/10.1016/j.ejphar.2005.03.037
Nagai T, Maeda T, Imai H, McGeer PL, McGeer EG (1985) Distribution of GABA-T-intensive neurons in the rat hindbrain. J Comp Neurol 231:260–269. https://doi.org/10.1002/cne.902310213
Palazzo E, Marabese I, de Novellis V, Oliva P, Rossi F, Berrino L, Rossi F, Maione S (2001) Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacol 40:319–326. https://doi.org/10.1016/s0028-3908(00)00160-x
Parvishan A, Taslimil Z, Ebrahimzadeh M, Haghparast A (2011) Capsazepine, a transient receptor potential vanilloid type 1 (TRPV1) antagonist, attenuates antinociceptive affect of CB1 receptor agonist, WIN55,212-2, in the rat nucleus cuneiformis. Basic Clin Neurosci 2:19–26
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, San Diego
Pertwee RG, Browne SE, Ross TM, Stretton CD (1991) An investigation of the involvement of GABA in certain pharmacological effects of delta-9-tetrahydrocannabinol. Pharmacol Biochem Behav 40:581–585. https://doi.org/10.1016/0091-3057(91)90366-A
Qu CL, Tang JS, Jia H (2006) Involvement of GABAergic modulation of antinociception induced by morphine microinjected into the ventrolateral orbital cortex. Brain Res 1073-1074:281–289. https://doi.org/10.1016/j.brainres.2005.12.067
Rashvand M, Khajavi A, Parviz M, Hasanein P, Keshavarz M (2014) GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala. Clin Exp Pharmacol Physiol 41:338–344
Rea K, Roche M, Finn DP (2007) Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate. Br J Pharmacol 152:633–648. https://doi.org/10.1038/sj.bjp.0707440
Rezvanipour M, Haghparast A, Millan H (2006) The role of GABAA receptor inhibitor on morphine antinociception action in cuneiformis nucleus. Int J Pharmacol 2:400–405. https://doi.org/10.3923/ijp.2006.400.405
Tjølsen A, Berge OG, Hunskaar S, Roslan JH, Hole K (1992) The formalin test: an evaluation of the method. Pain 51:5–17
Tsou K, Lowitz KA, Hohmann AG, Martin WJ, Hathaway CB, Bereiter DA, Walker JM (1996) Suppression of noxious stimulus-evoked expression of Fos protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Neuroscience 70:791–798
Vaughan CW, McGregor IS, Christie MJ (1999) Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol 127:935–940
Walker JM, Huang SM (2002) Cannabinoid analgesia. Pharmacol Ther 95:127–135. https://doi.org/10.1016/S0163-7258(02)00252-8
Wanigasekera V, Mezue M, Andersson J, Kong Y, Tracey I (2016) Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development. Anesthesiology 124:159–168. https://doi.org/10.1097/ALN.0000000000000924
Zendehdel M, Tirgari F, Shohre B, Deldar H, Hassanpour S (2017) Involvement of Gaba and cannabinoid receptors in central food intake regulation in neonatal layer chicks: role of CB1 and Gabaa receptors. Rev Bras Cienc Avic 19:221–230
Acknowledgments
The research leading to these results has received funding from the University of Zabol under grant agreement numbers UOZ-GR-9618-21 and UOZ-GR-9618-170.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chen, J., Hasanein, P., Komaki, A. et al. Effects of GABAA receptors in nucleus cuneiformis on the cannabinoid antinociception using the formalin test. Psychopharmacology 238, 1657–1669 (2021). https://doi.org/10.1007/s00213-021-05800-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05800-3