Rostral ventromedial medulla-mediated descending facilitation following P2X7 receptor activation is involved in the development of chronic post-operative pain

Abstract

Chronic postsurgical pain (CPSP) remains a medical problem. Whether the descending modulation of nociceptive transmission from the rostral ventromedial medulla (RVM) plays a role in CPSP induced by skin/muscle incision and retraction (SMIR) in the thigh is still unknown. In this study, we found that SMIR surgery, which induced either bilateral or unilateral mechanical allodynia, activated microglia, and up-regulated interleukin-1β (IL-1β), an important cytokine, and 8-hydroxyguanine, an oxidative stress marker in the RVM. In addition, the release of 5-hydroxytryptamine (5-HT) was increased in the ipsilateral and contralateral RVM in rats with either bilateral or unilateral pain following SMIR. The 5-HT level increase, 5-HT3 receptor (5-HT3R) up-regulation, and microglia activation were found bilaterally in SMIR rats with bilateral pain, but only ipsilaterally in SMIR rats with unilateral pain. The intrathecal injection of the 5-HT3R antagonist Y25130 prevented the development of CPSP and the activation of spinal microglia induced by SMIR. Furthermore, P2X7 receptor (P2X7R) was up-regulated in microglia in the RVM. The microinjection of the P2X7R antagonist brilliant blue G (BBG, a non-competitive P2X7R antagonist) into the RVM prevented the development of mechanical allodynia, inhibited the activation of microglia, and decreased the expression of IL-1β and 8-hydroxyguanine in the RVM following SMIR. Importantly, BBG injected into the RVM also decreased the activation of microglia and the level of 5-HT in the lumbar 3 (L3) spinal cord. The microinjection of the P2X7R agonist BzATP, the NADPH oxidase activator phorbol-12-myristate-13-acetate, or IL-1β into the RVM induced bilateral mechanical allodynia, microglia activation, and 5-HT release in the L3 spinal dorsal horn. Taken together, P2X7R activation in microglia in the RVM following SMIR might be responsible for the development of CPSP via activating descending serotonergic pathway. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Keywords: 5-hydroxytryptamine; Interleukin-1β; P2X7 receptors; chronic post-operative pain; microglia; rostral ventromedial medulla.