Activation of Orexin-A and Capsaicin Receptors in the Periaqueductal Gray is Ineffective in Reducing Mechanical Allodynia and Thermal Hyperalgesia in Rats

Document Type : Original Research

Authors
A. Sarihi 1
T. Shirafkan 2
A. Komaki 3
1 Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran, Postal code: 6517838736
2 Department of Biology, Faculty of Basic Sciences, Islamic Azad University of Hamadan, Iran
3 Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
Abstract
Introduction: Up to now, numerous neural circuits within the central nervous system have been identified as participants in the modulation of pain. Among these, the ventrolateral periaqueductal gray (vlPAG) region of the midbrain stands out as a crucial component of the pain modulation network at supraspinal levels. Its involvement has been extensively characterized across various animal pain models. In this research, we focused on investigating the roles of orexin A and capsaicin receptors within this region in mediating antinociceptive responses.

Methods: In this study, male Wistar rats were utilized to explore the antinociceptive effects of administering orexin-A and capsaicin directly into the ventrolateral periaqueductal gray (vlPAG) region of the midbrain. The substances were administered both separately and in combination. Then, their antinociceptive effects were assessed using the von Frey and hot plate tests post-injection. The experiments compared the outcomes of intra-vlPAG drug administration in both healthy control and diabetic animal models.

Results: Microinjections of orexin-A and capsaicin, whether administered individually or in combination directly into the PAG, failed to produce anti-nociceptive effects on mechanical allodynia or thermal hyperalgesia in both healthy and diabetic rats.

Conclusion: Acute microinjections of orexin-A and capsaicin did not produce significant anti-nociceptive effects in either healthy or kindled animal groups. To draw more accurate conclusions, it is recommended to investigate the long-term effects of these compounds as well.

Keywords

Subjects

[1] Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-84.
[2] Bouhassira D. Neuropathic pain: definition, assessment and epidemiology. Revue neurologique. 2019;175(1-2):16-25.
[3] Fox A, Eastwood C, Gentry C, Manning D, Urban L. Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. Pain. 1999;81(3):307-16.
[4] Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain. 1998;76(1-2):151-7.
[5] Said G. Diabetic neuropathy—a review. Nature clinical practice Neurology. 2007;3(6):331-40.
[6] Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573-85.
[7] de Lecea L, Kilduff T, Peyron C, Gao X-B, Foye P, Danielson P, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences. 1998;95(1):322-7.
[8] Chapa-Oliver AM, Mejía-Teniente L. Capsaicin: From plants to a cancer-suppressing agent. Molecules. 2016;21(8):931.
[9] Ghosh AK, Basu S. Tumor macrophages as a target for Capsaicin mediated immunotherapy. Cancer letters. 2012;324(1):91-7.
[10] Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation. 2005;112(23):3617-23.
[11] Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition: Elsevier; 2006.
[12] Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain. 1997;73(2):123-39.
[13] Robbins WR, Staats PS, Levine J, Fields HL, Allen RW, Campbell JN, et al. Treatment of intractable pain with topical large-dose capsaicin: preliminary report. Anesthesia & Analgesia. 1998;86(3):579-83.
[14] Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. Journal of Clinical Oncology. 1997;15(8):2974-80.
[15] Zis P, Apsokardos A, Isaia C, Sykioti P, Vadalouca A. Posttraumatic and postsurgical neuropathic pain responsive to treatment with capsaicin 8% topical patch. Pain Physician. 2014;17(2):E213.
[16] Watson CPN, Evans RJ, Watt VR, Birkett N. Post-herpetic neuralgia: 208 cases. Pain. 1988;35(3):289-97.
[17] Watson C, Tyler K, Bickers D, Millikan L, Smith S, Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clinical therapeutics. 1993;15(3):510-26.
[18] Kiani J, Sajedi F, Nasrollahi SA, Esna-Ashari F. A randomized clinical trial of efficacy and safety of the topical clonidine and capsaicin in the treatment of painful diabetic neuropathy. Journal of Research in Medical Sciences. 2015;20(4):359-63.
[19] Burness CB, McCormack PL. Capsaicin 8% patch: a review in peripheral neuropathic pain. Drugs. 2016;76:123-34.
[20] Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain. 1994;59(3):321-5.
[21] Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81(1-2):135-45.
[22] Ho Y-C, Lee H-J, Tung L-W, Liao Y-Y, Fu S-Y, Teng S-F, et al. Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. Journal of Neuroscience. 2011;31(41):14600-10.
[23] Esmaeili M-H, Reisi Z, Ezzatpanah S, Haghparast A. Functional interaction between orexin‐1 and CB 1 receptors in the periaqueductal gray matter during antinociception induced by chemical stimulation of the lateral hypothalamus in rats. European journal of pain. 2016;20(10):1753-62.
Pathobiology Reserach
Volume 26, Issue 2
April 2023
Pages 49-54