Grant: Operating Grant

Chronic, severe pain is a significant health problem. One third of North-Americans suffer from some form of chronic pain, and in over 30% it is resistant to analgesic therapy. The economic impact of pain is enormous, at approximately $ 100 billion annually. While non-steroidal anti-inflammatory drugs (NSAIDs) and opiate narcotics are effective for acute pain relief, adequate therapies for the treatment of chronic pain, including neuropoathic pain, complex regional pain syndrome, chemotherapy-induced pain, post-operative pain and inflammatory pain, are lacking. Medications currently used in the in the management of neuropathic pain states, such as tricyclic antidepressants, anticonvulsants (e.g. gabapentin), serotonin/noradrenalin reuptake inhibitors and opioid analgesics, are ineffective and produce side effects. There is convincing evidence that mitochondrial reactive oxygen species (ROS) and reactive nitrogen species (RNS) at the spinal level are involved in the generation and maintenance of neuropathic and inflammatory pain. Administration of various antioxidants (free radical quenchers) was somewhat effective in animal models of neuropathic pain, but very high doses were required because these agents were not targeted to mitochondria. A mitochondria-targeted mu opioid analgesic with antioxidant properties discovered in our laboratory, [Dmt1]DALDA, was found to be superior to morphine in animal models of neuropathic pain and complex regional pain syndrome, likely due to a synergistic effect between mu opioid- and antioxidant activity. We now propose to synthesize [Dmt1]DALDA analogues with further improved antioxidant capacity and to test them in vitro for opioid and antioxidant activity, and in vivo as pharmacological tools and drug candidates in animal models of the neuropathic pain states described above. The compounds to be developed are expected to be highly effective for neuropathic pain relief and to have low propensity to induce analgesic tolerance.