Efficacy and Spinal Noradrenergic Mechanisms of Contralateral Melittin Acupuncture Against Paclitaxel-Induced Peripheral Neuropathic Pain in Rats

Daxian Li,1 Fenqin Xue,2 Yan Wu,3,4 Lirong Chang,3 Yizhi Song,3 Xiaoqiang Du,3,5 Jie Wu,1 Qing Liu,1 Tianlong Wang1 1Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Core Facilities Center, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Neural Regeneration and Repair, Department of Anatomy, School of Basic Medical Sciences, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, People’s Republic of China; 4College of Veterinary Medicine, Beijing University of Agriculture, Beijing, People’s Republic of China; 5School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi Province, People’s Republic of ChinaCorrespondence: Tianlong Wang, Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, People’s Republic of China, Email [email protected]: Paclitaxel-induced peripheral neuropathy is a leading cause of premature discontinuation of taxane-based chemotherapeutic regimens. Studies have affirmed the analgesic properties of bee venom-containing pharmacoacupuncture, demonstrating that anti-nociceptive effects occur following melittin treatment at the ipsilateral ST36 (Zusanli acupoint). However, current understanding of the therapeutic potential of melittin-based approaches for the contralateral side is limited.Objective: This study comprehensively explored the analgesic potential and central mechanisms of melittin pharmacoacupuncture using behavioral, in vivo electrophysiological, and neuropharmacological techniques in rats with paclitaxel-induced peripheral neuropathy, focusing on the contralateral limb.Methods: Neuropathic signs following intraperitoneal paclitaxel regimens were quantified on the right-hind paw of rats using acetone drop and von Frey filament experiments. In vivo electrophysiological single-cell recordings of spinal wide-dynamic-range (WDR) neurons were made from the right-dorsal horn extracellularly (n=9– 10/group). Melittin was administered subcutaneously at the ST36 acupoint on the left-hind limb (n=7/group). For neuropharmacological analysis, prazosin (an α 1-adrenoceptor antagonist) or idazoxan (an α 2-adrenoceptor antagonist) was administered before apitherapy (n=6/group).Results: Following contralateral melittin treatments, a marked attenuation of peripheral cold and mechanical hypersensitivities, along with a sustained reversal of central sensitization in WDR neurons in response to peripheral cutaneous stimuli, was observed in neuropathic rodents after apitherapy. Melittin-induced analgesia involved central noradrenergic mechanisms: its effects on mechanical allodynia and hyperalgesia were counteracted by spinal α 2-adrenoceptor antagonism, and its effects on cold allodynia were dependent on activation of spinal α 1- and α 2-adrenoceptors.Conclusion: Applications of melittin to ST36 modulated spinal α 1- and α 2-adrenoceptors. This modulation induced a significant reorganization of nociceptive processing within dorsal horn pain-transmitting neurons, leading to attenuated neuropathic signs in the contralateral limb of rats. Collectively, our behavioral and neurophysiological findings provide pre-clinical evidence supporting melittin-based pharmacoacupuncture as a potential therapy for paclitaxel-induced neuropathic pain.Keywords: chemotherapy-induced peripheral neuropathy, apitherapy, analgesia, dorsal horn, in vivo recording, adrenoceptor