Molecules Acting on CB1 Receptor and their Effects on Morphine Withdrawal In Vitro

Abstract

Several pharmacological studies indicate that CB1 cannabinoid receptors (CB1Rs) are present in guinea pig ileum (GPI) and their activation reduce the acetylcholine (Ach) release. Dependence can be induced and measured in vitro by using GPI and the contraction due to opioid withdrawal is caused by acetylcholine release.Design of molecules acting on the CB1Rs are widely studied and the large availaibility of CB1Rs agonists and antagonists provides powerful tools to determine the role of these receptors in mediating some of physiological and pharmacological effects in the myenteric neurones.Given the relationship between CB1Rs/Opioid Withdrawal/Ach system, in the present paper we have designed six new CB1Rs agonists named A-F and evaluated their role in mediating morphine withdrawal in GPI. Also, a comparative study was performed by using the CB1Rs synthetic cannabinoid WIN 55,212-2 and CP 55,940. The results of our experiments indicate that both WIN 55,212-2 and CP 55,940 (1x10(-8)-5x10(-8)-1x10(-7) M) were able to reduce morphine withdrawal in a concentration-dependent manner. Very similar results were obtained with the new CB1Rs agonists (A-F) used at same concentrations. The results of our experiments indicate that CB1Rs are involved in the control of morphine withdrawal in vitro thus confirming an important functional interaction between the cannabinoid and opioid system.

Keywords: Ach. CB1 receptors; guinea-pig ileum.; morphine; withdrawal.

Fig. (1)

Typical tracing of opioid withdrawal on guinea-pig ileum. A. 3 similar acetylcholine response (A), electrical stimulation, injection of the opioid agonist (OA) followed after 4 min of contact period by naloxone (N) which induces contraction (1° opioid withdrawal). After washout (█), it was performed another A response. B: After 30 min resting period under electrical stimulation, a further 4 min exposure of the ileum to the OA and N elicited reproducible response (2° opioid withdrawal). C: After another 30 min resting period under electrical stimulation, the ileum responded again to the OA and N with the same intensity (3° opioid withdrawal).