Morphine and ?9-tetrahydrocannabinol: Two-way cross tolerance for antinociceptive and heart-rate responses in the rat

Abstract

Tail-flick analgesic responses and heart-rate changes were measured in male Sprague-Dawley rats challenged with an acute IP morphine sulfate (MS) or Δ⁹-THC injection after receiving daily injections of Δ⁹-THC or morphine, respectively. Degree of tolerance development to each agent was determined before the cross-tolerance challenge was administered. Cross tolerance occurred to analgesic and bradycardic effects of a 10 mg/kg THC challenge in rats receiving 50 mg/kg MS injections over a 23-day period. Cross tolerance to the bradycardic effects of a 20 mg/kg MS challenge occurred in rats receiving seven daily 10 mg/kg Δ⁹-THC injections and to MS tail-flick analgesia after 14 days. Although rapid tolerance occurred during administration of both agents, cross tolerance to THC bradycardia occurred only in groups exhibiting complete tolerance to MS injections; cross tolerance to MS bradycardia was observed in animals that were only partially tolerant to THC injections. The data extend earlier cross tolerance data in the mouse to the rat, and provide new information using heart rate, a response that may mirror aversive internal states induced by drugs.