The Effect of Clonidine Pretreatment on Epidural Resiniferatoxin in a Neuropathic Pain Rat Model

Resiniferatoxin (RTX) is an ultrapotent synthetic TRPV1 (transient receptor potential vanilloid subtype 1) agonist with significant initial transient hyperalgesia followed by a prolonged analgesic effect in response to thermal stimulus. Using a rat model of neuropathic pain, we evaluated the effect of pretreatment with clonidine－which has been shown to relieve intradermal capsaicin-induced hyperalgesia－on the initial hyperalgesic response and the thermal analgesic property of RTX. Thirty-six male rats were divided into 6 treatment groups (n＝6 each):RTX 500ng, RTX 1μg, clonidine 20μg (Cl), Cl＋RTX 500ng, Cl＋RTX 1μg, or normal saline 20μL (control). We evaluated the short-term (180min) and long-term (20 days) analgesic effects of RTX after thermal stimulation and mechanical stimulation. RTX had significant initial transient hyperalgesia followed by a prolonged analgesic effect in response to the thermal stimulus, but the RTX 500ng and RTX 1μg groups showed no initial short-term thermal hyperalgesic responses when pretreated with clonidine. The Cl＋RTX 1μg ratsʼ behavior scores indicated that they were more calm and comfortable compared to the RTX 1μg rats. Even though we cannot precisely confirm that pretreatment with clonidine potentiates or adds to the analgesic effect of RTX, clonidine pretreatment with epidural RTX eliminated the initial RTX-associated hyperalgesic response and systemic toxicity in this neuropathic pain rat model.