Activation of
opioid and
cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of
opioid and
cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of
DAMGO, a selective agonist for μ-
opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of
DAMGO and ACPA in attenuating complete
Freund's adjuvant (CFA)-induced
mechanical hyperalgesia in the rat hindpaw.
DAMGO (1μg-1mg) or ACPA (1μg-2mg) was administered into the inflamed paw when
mechanical hyperalgesia was fully developed. When administered individually,
DAMGO and ACPA dose-dependently reversed the
mechanical hyperalgesia.
DAMGO displayed a lower ED50 value (57.4±2.49μg) than ACPA (111.6±2.18μg), but ACPA produced longer lasting antihyperalgesic effects. Combinations of
DAMGO and ACPA also dose-dependently attenuated
mechanical hyperalgesia, but the antihyperalgesic effects were partial and transient even at high doses. Using isobolographic analysis, we determined that combined treatment with
DAMGO and ACPA produced antagonistic effects with the observed ED50 of 128.4±2.28μg. Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate
mechanical hyperalgesia when administered individually, but exert opposing effects when administered together. The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined
drug treatments in
chronic pain conditions can be optimized.