Evidence of involvement of the nNOS and the kappa-opioid receptor in the same intracellular network of the rat periaqueductal gray that controls morphine tolerance and dependence

Abstract

Tolerance and dependence are the most important side effects of opioid-mediated pain therapies. However, the mechanisms through which these phenomena are produced still remain unknown. Among the opioid receptors, the kappa-opioid receptor has been the focus of strong research efforts, since it contributes to the reversal of morphine-induced tolerance and dependence. Parallel to this, neuronal nitric oxide synthase has been shown to play a key role in the development of these unwanted effects. Both the kappa-opioid receptor and neuronal nitric oxide synthase are abundantly located in the CNS. One of the areas where these cellular agents are best represented is a key encephalic nucleus in the development of tolerance to the analgesic action of opioid drugs, the periaqueductal gray. In this work, we studied whether morphine-induced tolerance and dependence causes changes (a) in the activity of neuronal nitric oxide synthase and (b) in kappa-opioid receptor expression in the rat periaqueductal gray. Besides, we examined the colocalization of both molecules. Our results point to an involvement of KOR and nNOS in the same intracellular network that controls the development of morphine tolerance and dependence.