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

Background: 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 α1-adrenoceptor antagonist) or idazoxan (an α2-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 α2-adrenoceptor antagonism, and its effects on cold allodynia were dependent on activation of spinal α1- and α2-adrenoceptors. Conclusion: Applications of melittin to ST36 modulated spinal α1- and α2-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.