Repeated Tetrahydrocannabinol Injections Induce Tolerance but Do Not Disrupt Ongoing Behaviour Upon Withdrawal in Male and Female Rats With Inflammatory Pain.

Inflammatory pain, induced by CFA injection in rats, reduced wheel running. Twice-daily THC injections (3 mg/kg) further decreased running in both sexes, with tolerance developing more strongly in males. No spontaneous withdrawal was observed over six days, nor any effect on body weight. The absence of withdrawal contrasts with previous opioid findings where pain enhanced morphine withdrawal. Persistent inflammatory pain does not alter the effects of repeated THC in male or female rats; THC's use for pain is limited by side effects and tolerance but not by dependence-related withdrawal.

Study at a glance

Abstract

Many people use cannabis to self-medicate for pain. Little is known about the impact of pain on tolerance and spontaneous withdrawal to delta-9-tetrahydrocannabinal (THC), the primary psychoactive compound in cannabis. Our previous research with the opioid morphine suggests persistent pain will increase the magnitude and duration of THC withdrawal. Male and female Sprague-Dawley rats were individually housed in a cage with a running wheel to provide a continuous and objective measure of well-being. All rats were injected with Complete Freund's Adjuvant (CFA) into the right hindpaw to induce inflammatory pain. Beginning 1 day later, rats received twice daily THC or vehicle injections for 7 days followed by assessment of tolerance and spontaneous withdrawal. Administration of CFA decreased wheel running. Twice daily injections of THC (3 mg/kg/injection) caused a further reduction in running in male and female rats. Tolerance to the THC-induced decrease in running was more pronounced in male compared to female rats. There was no evidence of spontaneous withdrawal to THC despite continuous assessment for 6 days. Likewise, withdrawal had no effect on body weight. The lack of spontaneous withdrawal in rats with hindpaw inflammation is consistent with our recent study showing a lack of spontaneous withdrawal to THC in pain free rats, but opposite to our opioid research showing enhancement of spontaneous withdrawal to morphine in rats with hindpaw inflammation. In sum, persistent inflammatory pain does not appear to alter the effects of repeated THC injections in male or female rats. The use of THC as a treatment for pain is limited by side effects and tolerance but not by dependence associated withdrawal symptoms.