Role of Spinal Neurotransmitter Receptors in Itch: New Insights into Therapies and Drug Development

Targets for antipruritic therapies are now expanding from the skin to the central nervous system. Recent studies demonstrate that various neuronal receptors in the spinal cord are involved in pruritus. The spinal opioid receptor is one of the best-known examples. Spinal administration of morphine is frequently accompanied by segmental pruritus. In addition to mu-opioid receptor antagonists, k-opioid receptor agonists have recently come into usage as novel antipruritic drugs, and are expected to suppress certain subtypes of itch such as hemodialysis- and cholestasis-associated itch that are difficult to treat with antihistamines. The gastrin-releasing peptide receptor in the superficial dorsal horn of the spinal cord has also received recent attention as a novel pathway of itch-selective neural transmission. The NMDA glutamate receptor appears to be another potential target for the treatment of itch, especially in terms of central sensitization. The development of NMDA receptor antagonists with less undesirable side effects on the central nervous system might be beneficial for antipruritic therapies. Drugs suppressing presynaptic glutamate-release such as gabapentin and pregabalin also reportedly inhibit certain subtypes of itch such as brachioradial pruritus. Spinal receptors of other neuromediators such as bradykinin, substance P, serotonin, and histamine may also be potential targets for antipruritic therapies, given that most of these molecules interfere not only with pain, but also with itch transmission or regulation. Thus, the identification of itch-specific receptors and understanding itch-related circuits in the spinal cord may be innovative strategies for the development of novel antipruritic drugs.