Delta and kappa opioid receptors as suitable drug targets for pain

Similar to μ opioid receptors, κ and δ opioid receptors reside in the periphery, the dorsal root ganglion, the spinal cord, and in supraspinal regions associated with pain modulation. Both δ and κ 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 κ receptors, and none that target δ receptors. Spurred by the need for an efficacious analgesic without the unwanted side effects associated with the typical clinical profile of μ opioid agonists, new research has provided insight into why the development of effective κ and δ opioid receptor agonists has remained elusive thus far, and importantly, how these obstacles may be overcome. For example, for δ opioid agonists to be effective, a state of inflammation may be required as this induces δ opioid receptors to migrate to the surface of neuronal cells and thereby become accessible to δ opioid agonists. Studies have shown that δ opioid agonists can provide relief of inflammatory pain and malignant bone pain. Meanwhile, peripherally restricted κ opioid agonists have been developed to target κ 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 μ opioid receptor agonists makes δ and peripherally restricted κ opioid receptor agonists promising targets for treating pain.