This proposal is based on the hypothesis that a molecule which has CCK receptor antagonist actions and opioid agonist actions will offer therapeutic advantage for the management of the pathological pain states associated with nerve injury (i.e., neuropathic pain), as well as acute pain, with minimal (or no) development of tolerance and physical dependence. CCK is an endogenous """"""""antiopioid"""""""" which blocks morphine antinociception. CCK antagonists enhance morphine antinociception and block morphine antinociceptive tolerance. Levels, and/or availability, of spinal CCK are believed to be differentially altered by neuropathic or inflammatory pain suggesting the importance of CCK in pathological states to limit the actions of opioids for pain relief. Thus, inflammation has been suggested to decrease spinal CCK levels/availability and enhance morphine antinociception, while nerve-injury increases spinal CCK levels/availability and decrease morphine antinociception. We propose to exploit these known opioid-CCK interactions in nerve-injury associated nociception (i.e., """"""""pain""""""""), as well as in acute pain, by testing the hypothesis that bifunctional molecules with a profile of CCK antagonist and opioid agonist can be discovered and be of therapeutic benefit for acute and nerve-injury related pain without significant development of antinociceptive tolerance and, possibly, without or with reduced physical dependence. This hypothesis will be tested by synthetic efforts aimed at modifying the structure of our lead compound, SNF 9007, which displays low nM affinity for CCKB and delta opioid receptors and agonist activity at both sites. Our synthetic efforts will attempt to discover a molecule which has high affinity and antagonist properties at CCKA or CCKB receptors (i.e., """"""""balanced"""""""" CCK receptor antagonist) and high affinity and agonist properties at opioid mu or delta receptors. Novel molecules will be evaluated for affinity at CCK and opioid receptors, as well as agonist/antagonist activity at these receptors. Appropriate candidates will then be evaluated in both acute and nerve-injury associated nociception. Single and repeated administration of the molecules will be performed to evaluate the possible development of antinociceptive tolerance, and possible physical dependence will be determined by precipitation with naloxone. It is expected that this work will lead to novel and potentially useful medications for treatment of (a) neuropathic and acute pain (b) chronic pain without tolerance and (c) pain in those tolerant to opioids. This novel mechanism of action should yield therapeutic utility as well as provide an increased understanding of opioid-CCK interactions in normal and pathological pain states.
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