Cannabinoid Modulation of the Behavioral Effects of Morphine

Researchers have demonstrated interactions between exogenously administered cannabinoid and opioid ligands on a variety on behavioral endpoints. The following studies extend these findings by examining the role of the endogenous cannabinoid system in the antinociceptive, and other behavioral effects of morphine. The experiments in Chapter 2 use disruption of signaling via the type 1 cannabinoid receptor (CB1) in order to examine the role of the endogenous cannabinoid system in the antinociceptive effects of morphine. The effects of morphine did not differ in CB1 KO and WT mice; however, a CB1 antagonist did attenuate the effects of morphine. This suggests that endogenous cannabinoid signaling via CB1 receptors modulates the antinociceptive effects of morphine, and CB1 KO mice may undergo developmental changes that mask this role. The experiments described in Chapter 3 examine the consequences of the enhancement of endogenous cannabinoid signaling on the antinociceptive effects of morphine. This was accomplished by examining morphine alone and in combination with drugs that inhibit the degradation of the endogenous cannabinoid anandamide (AEA). Two well-established preclinical pain models, the hotplate assay and the acetic acid-induced writhing assay, were used in these studies. The results demonstrate that inhibition of the enzymatic breakdown of endogenous cannabinoids enhances the antinociceptive effects of morphine in the acetic acid-induced writhing assay, but not the hotplate assay. Chapter 4 assesses morphine in combination with the same pharmacological manipulations of endogenous cannabinoid signaling that were described in Chapter 3. These experiments extend the previous results by examining these drug combinations in assays of pain-suppressed behavior and schedule-controlled behavior. The results provide evidence that, unlike direct CB1 agonists, drugs that alter endogenous cannabinoid levels specifically alter morphine's antinociceptive effects. The experimental results described in this dissertation suggest that the endogenous cannabinoid system plays a role in the antinociceptive effects of morphine. In addition, these findings show that this role is dependent on variables such as the nature of the noxious stimulus, and the means used to prevent endogenous cannabinoid degradation. Finally, these studies suggest that this enhancement of morphine's behavioral effects is limited to antinociception