Low-Dose Δ9-THC Produces Antinociception in Female, But Not Male Rats

Abstract

Introduction: The analgesic effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, have been widely promoted. Unfortunately, animal research is limited by the use of high doses and pain-evoked tests. Motor and psychoactive effects of THC may suppress evoked responses in the absence of antinociceptive effects. Materials and Methods: This study overcomes these problems by assessing the antinociceptive effect of low doses of subcutaneous THC on depression of home cage wheel running caused by hindpaw inflammation. Female and male Long-Evans rats were individually housed in a cage with a running wheel. Results: Female rats ran significantly more than male rats. Administration of Complete Freund's Adjuvant into the right hindpaw produced inflammatory pain that significantly depressed wheel running in female and male rats. Administration of a low dose of THC (0.32, but not 0.56 or 1.0 mg/kg) restored wheel running in the hour after administration in female rats. Administration of these doses had no effect on pain-depressed wheel running in male rats. Conclusions: These data are consistent with previous studies showing greater antinociceptive effects of THC in female compared with male rats. These data extend previous findings by showing that low doses of THC can restore pain-depressed behaviors.

Keywords: analgesia; cannabis; pain-depressed behavior; sex difference; wheel running.

FIG. 1.

Female rats (N=31) had higher levels of baseline running than male rats (N=43). Most running occurred during the dark phase (0–12 h) compared with the light phase (13–18 h). Data are presented as total running in 3 h bins. *Significant sex differences (Fisher's LSD post hoc comparison, p<0.01). LSD, Least Significant Differences.

FIG. 2.

Hindpaw inflammation reduced running in female and male rats. Administration of CFA into the hindpaw reduced the number of wheel revolutions during the normally active dark phase in female and male Long-Evans rats. Data are presented as total wheel revolutions during the 12 h dark phase. *Significant sex differences (Fisher's LSD post hoc comparison, p<0.05). CFA, Complete Freund's Adjuvant.

FIG. 3.

Low-dose THC administration restored wheel running in female rats. All rats had low levels of wheel running because of hindpaw inflammation. Administration of THC increased wheel running in female rats compared with vehicle-treated rats and male rats treated with THC. THC was administered immediately before the beginning of the dark phase. The effects of THC were assessed for the first hour of wheel running during the dark phase. Sample size was 6–9 rats/dose for female rats and 9–12 for male rats. *Significant sex difference. THC, delta-9-tetrahydrocannabinol.