Suppression of neuropathic pain in the circadian clock-deficient [Per2.sup.m/m] mice involves up-regulation of endocannabinoid system

• Published in: PNAS nexus 2024-01, Vol.3 (1)
• Main Authors: Yamakawa, Wakaba, Yasukochi, Sai, Tsurudome, Yuya, Kusunose, Naoki, Yamaguchi, Yuta, Tsuruta, Akito, Matsunaga, Naoya, Ushijima, Kentaro, Koyanagi, Satoru, Ohdo, Shigehiro
• Format: Article
• Language: English
• Subjects: Biological products industry; Genes; Scientific equipment and supplies industry
• ISSN: 2752-6542; 2752-6542
• DOI: 10.1093/pnasnexus/pgad482

Neuropathic pain often results from injuries and diseases that affect the somatosensory system. Disruption of the circadian clock has been implicated in the exacerbation of the neuropathic pain state. However, in this study, we report that mice deficient in a core clock component Period2 ([Per2.sup.m/m] mice) fail to develop tactile pain hypersensitivity even following peripheral nerve injury. Similar to male wild-type mice, partial sciatic nerve ligation (PSL)-[Per2.sup.m/m] male mice showed activation of glial cells in the dorsal horn of the spinal cord and increased expression of pain-related genes. Interestingly, [alpha]1D- adrenergic receptor ([alpha]1D-AR) expression was up-regulated in the spinal cord of [Per2.sup.m/m] mice, leading to increased production of 2- arachidonoylglycerol (2-AG), an endocannabinoid receptor ligand. This increase in 2-AG suppressed the PSL-induced tactile pain hypersensitivity. Furthermore, intraspinal dorsal horn injection of adeno-associated viral vectors expressing [alpha]1D-AR also attenuated pain hypersensitivity in PSL-wild-type male mice by increasing 2-AG production. Our findings reveal an uncovered role of the circadian clock in neuropathic pain disorders and suggest a link between [alpha]1D-AR signaling and the endocannabinoid system. Keywords: circadian clock, clock gene, Period2, neuropathic pain, [alpha]1D- adrenergic receptor, 2-arachidonoylglycerol, endocannabinoid system