Opioids: old drugs for potential new applications

Opioids are commonly used analgesics in clinical practice. Three opioid receptors (mu, delta and kappa) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although mu opioid receptors are the major receptor to mediate the analgesic effects of opioids, delta and kappa receptors are also important in anti-nociception (for example, delta and kappa receptors can mediate spinal analgesia). Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by delta receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by delta receptors, G(i/o) proteins, protein kinase C, ATP-sensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves delta(1) receptors, mitochondrial ATP-sensitive potassium channels and free radical production. In this review, we will briefly describe the analgesic effects of opioids. We will focus our discussion on opioid preconditioning-induced protection and its mechanisms. Opioids and agents that specifically work on the signaling molecules for opioid preconditioning-induced protection may prove to be useful in inducing protection against ischemia in clinical practice.