Morphine and Delta‐9‐Tetrahydrocannabinol Antinociceptive Interactions in Male versus Female Rats with Inflammatory Pain
Authors: Britch Stevie , Wiley Jenny , Craft Rebecca 
Published: June 2021

Previous studies have shown that morphine is more potent in male rats compared to females with chronic inflammatory pain. In contrast, delta‐9‐tetrahydrocannabinol (THC) may be more potent in females compared to males with chronic inflammatory pain. Some studies have demonstrated that morphine and THC produce synergistic antinociceptive effects in male animals. Therefore, the purpose of the present study was to determine sex‐specific potency of morphine and THC in male versus female rats with inflammatory pain, and then to test for antinociceptive synergy between morphine and THC.

Male and female Sprague Dawley rats, 60–90 days old were used. On day 1 baseline measurements were taken on the von Frey test of mechanical allodynia, incapacitance test of biased weight bearing, a 10‐min locomotor activity test, and right hindpaw thickness. After baseline testing, inflammation was induced by an intraplantar injection of complete Freund's adjuvant (CFA) to the right hindpaw. Three days later, morphine (0, 0.1, 0.32, 1.0, or 3.2 mg/kg, s.c.) or THC (0, 0.5, 1.0, 2.0, or 4.0 mg/kg, i.p.) was administered and nociceptive testing was conducted at 30, 60, 120, and 240 min post‐injection. Paw thickness was also measured at 240 min post‐injection. A three‐way ANOVA was conducted on means of the 30–120 min time point data to determine sex differences in the antinociceptive effects of morphine alone and THC alone. The ED50 was calculated for morphine and for THC in each sex using data from the von Frey test. These data were used to determine 1:1, 3:1, and 1:3 dose‐addition ratios for each sex, which were administered in Experiment 2 under the same testing protocol as in Experiment 1.

In both sexes, CFA increased right hindpaw thickness to approximately 200% of baseline, as well as causing mechanical allodynia, biased weight‐bearing, and decreased locomotor activity. In Experiment 1, morphine given alone dose‐dependently reduced mechanical allodynia similarly in both sexes. Morphine also dose‐dependently reduced biased weight‐bearing in both sexes, and was more potent in males than females. Morphine did not significantly alter paw thickness or locomotor activity in either sex. THC given alone dose‐dependently reduced allodynia and decreased locomotor activity similarly in males and females, but did not alter biased weight‐bearing or paw thickness in either sex. In Experiment 2, a 1:1 combination of morphine and THC produced large anti‐allodynic effects in both sexes. A dose‐addition analysis will be conducted when data collection is complete.

Results thus far indicate that THC alone may be a beneficial analgesic to treat chronic inflammatory pain in both sexes, but may also produce sedation, a negative side effect. Similar to previous reports in rats, morphine alone also alleviates persistent inflammatory pain, but with greater potency in males than females. Given the sex differences observed with each drug alone, we predict that morphine‐THC combinations will produce greater antinociception in males compared to females.

Support or Funding Information

This research was supported by funds from the National Institute on Drug Abuse (DA016644).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.