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The research activities of the Inturrisi laboratory are directed toward the development of methods for the alleviation of pain. The laboratory is investigating the role of glutamate receptors in the neuronal plasticity that is manifest as injury-induced pain as well as opioid tolerance, dependence and addictive behaviors. We have used the loxP-Cre technology to produce a gene deletion (conditional knockout) of the NMDAR1 subunit of the NMDA glutamate receptor or the GluR2 subunit of the AMPA glutamate receptor in targeted areas of CNS of an adult mouse.  When the conditional knockout is confined to the lumbar spinal cord, the knockout mice exhibit normal motor, tactile and acute protective pain thresholds. However, the spinal cord dorsal horn pain transmission system no longer produces NMDA currents and the mice are protected from injury-induced pain. This model is being extended to other glutamatergic receptors (AMPA) and other effects (spinal opioid tolerance). The role of glutamate receptors in the addictive behaviors resulting from the administration of cocaine and opioids and mediated by the mesolimbic dopamine system are being investigated by preparing conditional knockouts of NMDA and AMPA receptors in the nucleus accumbens and ventral tegmental reward areas of the brain. We are also developing viral vectors to deliver RNAi sequences intended to silence the expression of genes involved in pain transmission.

At the clinical level, our group discovered that the d isomer of methadone is a nonopioid, NMDA receptor antagonist in animal studies and we now plan to evaluate the safety and efficacy of this compound in patients with pain. These studies are intended to discover new treatments for pain and drug addiction.