Abstract
Cannabinoids and opioids are two of the oldest known categories of drugs, used for their medicinal and recreational properties since ancient times. Drugs belonging to these two classes have similar molecular mechanisms of actions and thus show a number of overlapping pharmacological effects and adverse effects. One of these overlapping effects of cannabinoids and kappa opioids is dose dependent increase in diuresis in rodents, non human primates and even humans, believed to be due to the suppression of vasopressin levels. In order to determine whether the endocannabinoid and kappa opioid system interact in any significant manner we tested the effects of chronic Δ<sup>9</sup>-tetrahydrocannabinol (THC) dosing on diuresis caused by CB1 agonist, AM4054 and kappa opioid, U50488 in mice. The diuretic effects in mice were measured over a period of 6 hours and diuresis was measured before chronic THC dosing (baseline) and on day 1, day 7 and day 14 post chronic 7 day THC dosing. The results showed that chronic THC tolerance caused a 3.5 to 4.5-fold rightward shift in the AM4054 diuretic dose response curve (for both the ascending and descending limbs). The baseline diuretic dose response was almost completely recovered within 14 days after cessation of THC dosing. The study of U50488 in THC tolerant mice showed an unusual flattening of the diuretic dose effect function, which was not completely reversed even at 14 days post termination of chronic THC dosing. Testing the effects of THC tolerance on diuresis caused by furosemide indicated that there was no significant difference in the diuretic effect of furosemide in normal and THC tolerant mice. From the results we concluded that AM4054 and THC are cross tolerant for their diuretic effect and further investigation of tolerance to other cannabinoid effects like antinociception and hypothermia is warranted. The flattening of the dose effect function of U50488 indicates that THC might be interfering with kappa opioid diuresis in a longer lasting manner than normal tolerance.
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