G. W. Terman, M.D., Ph.D.
For the last several years my laboratory has studied the neurochemical changes that take place in the neonatal rat spinal cord following repeated opiate administration as a cellular model of opiate analgesic tolerance. We have reported NMDA receptor-mediated increases in nociceptive primary afferent synaptic transmission associated with opiate tolerance. We have also discovered that the endocannabinoid 2-arachidonoylglycerol (2-AG), released in response to increased nociceptor activity, feeds back to inhibit such activity by acting at presynaptic CB1 receptors. Recently, we found that, like nociception, itch sensation, also appears to be increased in animals previously exposed to repeated morphine injections, although this effect is largely masked by concurrent spinal endocannabinoid inhibition. After intrathecal adminstration of the CB1 receptor antagonist SR141716 (SR) significant increases in scratching behaviors are observed — particularly in rats previously treated with repeated morphine injections. We hypothesize that repeated opiate administration induces central sensitization of primary afferent neurotransmission of pruritus, thereby increasing the synthesis and release of 2-AG, which in turn feeds back to inhibit itch by binding to presynaptic CB1 receptors. The current application proposes to begin testing this hypothesis with two specific aims:
Such studies may suggest novel anti-pruritic therapies for cannabinoids as well as providing new models and concepts to investigate the neural underpinnings of spinal interactions between pain and itch.