Research Project
6736602
DESCRIPTION (provided by applicant): The proposed work will test the efficacy of proprietary combinations of opioid agonists and ultra-low-dose opioid antagonists in a rat model of neuropathic pain. A large body of work in rodent nociception assays has established that the addition of an ultra-low-dose opioid antagonist enhances the analgesic potency of the opioid agonist and also alleviates the analgesic tolerance and somatic withdrawal effects that accompany chronic administration of opioid agonists. These opioid agonist/antagonist combinations are currently in development by Pain Therapeutics, Inc. for non-neuropathic pain. Eiectrophysiological work supports the theory that ultra-low-dose opioid antagonists prevent opioid tolerance by blocking opioid receptors that have switched their signaling from an inhibitory to an excitatory mode that elicits hyperalgesia. In addition, it is hypothesized that similar excitatory signaling of opioid receptors underlies the paradoxical hyperalgesia caused by low doses of opioid agonists; ultra-low doses of opioid antagonists also convert this hyperalgesia to analgesia. Importantly, neuropathic pain and hyperalgesia from either morphine tolerance or low doses of morphine activate descending pain facilitatory pathways and cause release of dynorphin in the spinal cord. In addition to assessing efficacy of opioid agonist/antagonist combinations in a neuropathic pain model, it is the aim of this proposal to measure the effects of this drug treatment on mechanisms of neuropathic pain and opioid tolerance. Efficacy will be assessed by measuring thermal hyperalgesia and tactile allodynia in L5/L6 spinal nerve ligated rats administered morphine or morphine + ultra-low-dose naltrexone for 7 days. Mechanistically, co-immunoprecipitation of the receptor and G alpha subunits will define G-protein signaling changes that may occur in opioid tolerance and/or in neuropathic pain; these studies will measure the activity of opioid agonist/antagonist combinations to prevent such cellular changes. Finally, on a systems level, quantification of spinal dynorphin will assess whether this opioid agonist/antagonist treatment can prevent the increase in spinal dynorphin that is a result of activation of descending pain facilitatory pathways in neuropathic pain and in opioid antinociceptive tolerance. Moreover, analgesia for neuropathic pain is a large unmet medical need, and there is strong rationale for this investigation.
