[A new turn of research for morphine dependence]

The World Health Organization (WHO) developed practical guidelines for pain relief in cancer patients in 1986. Although morphine is a standard opioid analgesic with sufficient analgesic potency, it also has undesirable effects such as drug dependence. Considering the significant of the management of patients with chronic cancer pain, it is no exaggeration to say that the investigation of morphine dependence is now most required research for pain relief. Various studies provide arguments to support substantial roles for mu-opioid receptors associated with the mesolimbic dopaminergic pathway and the possible involvement of delta-opioid receptors in the rewarding effect by morphine in animals. By contrast, the activation of kappa-opioid receptors leads to the suppression of this effect of morphine. It is noteworthy that chronic inflammatory nociception enhances endogenous kappa-opioidergic system, leading to the suppression of rewarding effects of morphine. These results obtained from the basic research strongly reflect the clinical results that psychological dependence on morphine is not a major concern when morphine is used to control pain for cancer patients. Another limiting factor in the clinical utilization of opioids is that repeated administration leads to the development of tolerance to opioids. At the cellular level, phosphorylation of opioid receptors by protein kinases, especially G-protein-coupled receptor kinase (GRK) and protein kinase C (PKC), is likely to play a major role in these tolerant and dependent states. We recently found that repeated administration of mu-agonist causes a down regulation of mu-receptor-mediated G-protein activation, which is associated with a specific upregulation of PKC gamma isoform. We therefore propose that PKC gamma may play a critical role in the development of morphine tolerance.