Delta and kappa opioid receptors as suitable drug targets for pain

Abstract

Similar to mu opioid receptors, kappa and delta opioid receptors reside in the periphery, the dorsal root ganglion, the spinal cord, and in supraspinal regions associated with pain modulation. Both delta and kappa opioid agonists have been shown to activate pain inhibitory pathways in the central nervous system. Yet, currently there are only a few pharmacologic agents that target kappa receptors, and none that target delta receptors. Spurred by the need for an efficacious analgesic without the unwanted side effects associated with the typical clinical profile of mu opioid agonists, new research has provided insight into why the development of effective kappa and delta opioid receptor agonists has remained elusive thus far, and importantly, how these obstacles may be overcome. For example, for delta opioid agonists to be effective, a state of inflammation may be required as this induces delta opioid receptors to migrate to the surface of neuronal cells and thereby become accessible to delta opioid agonists. Studies have shown that delta opioid agonists can provide relief of inflammatory pain and malignant bone pain. Meanwhile, peripherally restricted kappa opioid agonists have been developed to target kappa opioid receptors located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain. The recently shown efficacy of these analgesics combined with a possible lower abuse potential and side effect burden than mu opioid receptor agonists makes delta and peripherally restricted kappa opioid receptor agonists promising targets for treating pain.