Neural Responses to Injury: Prevention, Protection, and Repair

Studies in the Division of Neuropharmacology investigated the role of endogenous opioid systems in learning and memory, ventilatory function and antinociception. The goal of these studies was: to identify and characterize candidate ligands that might be useful in studies on delta opioid mechanisms; and to use these compounds to systematically investigate the role of delta systems in complex behavioral processes, in respiration and in the perception of noxious stimuli. The first candidate compound was BW373U86, which is a highly-selective agonist for the delta opioid receptor. BW373U86 had effects that differed from those of other prototypic opioid agonists. BW373U86 failed to produce antinociceptive effects in rhesus monkeys. Although BW373U86 had effects that were unique from the effects obtained with prototypic mu or kappa opioid agonists, the behavioral and pharmacological profile for this agonist was disappointing. A second candidate compound which was focused upon was OHM3507. This compound differs from morphine in that it does not suppress the immune system. It was hypothesized that this differences might be due to activity at the delta opioid receptor. The pharmacologic and behavioral effects of the fentanyl derivative OHM3507 were assessed to determine if this compound had increased antinociceptive effects and a reduced number of undesirable effects (e.g., respiratory depression) as compared to the prototypic opioids (e.g., fentanyl, morphine). Studies were undertaken to determine the opioid receptor selectivity of OHM3507 using behavioral assays in rhesus monkey. At a dose of 0.32 mg/kg, OHM3507 produced 100% antinociception (20s latency) in monkeys and reduced minute volume respiration to <60% in both air and 5% C02 in 02. In subjects treated daily with morphine (3.2 mg/kg) discriminating between saline and 0.01 mg/kg naltrexone, OHM3507 attenuated responding on the naltrexone-associated lever in a dose-dependent manner. OHM3507 decreased the rate of responding at doses greater than 0.1 mg/kg, but did not disrupt learning or performance of a complex behavioral task in monkeys. The administration of naltrexone dose-dependently shifted the OHM3507 dose-effect curve to the right with pA2s of 7.8 and 8.2 for antinociception and discrimination, respectively. OHM3507 produced 100% antinociception at 3.2 mg/kg. These data suggest that: 1) OHM3507 produces fentanyl-like effects at the u opioid receptor in rhesus monkeys, in contrast to its effects in rodents; 2) the reported lack of NK-cell activity after OHM3507 administration suggests a reduced risk of immunosuppression produced by this chemical class and 3) there is a necessity to study this class of compounds under a variety of experimental conditions in different species in order to better characterize the properties of these compounds and their potential clinical values, however, our studies indicate that they are devoid of delta opioid receptor activity. The highly selective nonpeptidic ligand, SNC-80 was the third candidate compound investigated. This compound is the methyl ether of one enantiomer of BW373U86, but differs from BW373U86 in that it is systemically active and has demonstrated selectivity for the delta receptor that is comparable to that seen with cfe/ta-selective opioid peptides. In the ventilation studies, 0.1-1 mg/kg of SNC-80 decreased all three measures of respiration in air in a dose-related manner. Interestingly, and in contrast to the effects of some typical mu opioids, the effects of SNC-80 on ventilation in air were larger than the effects on ventilation in 5% C02. At a dose of 1 mg/kg, SNC80 decreased minute volume in air to less than 50% of control in air. In antinociceptive studies, doses of SNC-80 as high as 3.2, mg/kg failed to produce an antinociceptive effect in any of the four rhesus monkeys studied. This lack of antinociceptive effect with SNC-80 were consistent with results obtained previously with BW373U86. Studies also determined whether a similar range of doses of SNC-80 could disrupt measures of rate and accuracy in monkeys responding under a multiple schedule of learning and performance. In each of the monkeys tested, SNC-80 (0.1-5.6 mg/kg) dose-dependently decreased the overall rate of responding in both components, and selectively decreased the accuracy of responding in the learning component. The effects of SNC-80 on the accuracy of responding were selective in that it produced small error-increasing effects in acquisition, but failed to produce any error-increasing effects in performance across the same dose range. In summary, these data suggest that SNC-80 produces BW373U86-like behavioral effects at delta opioid receptors in rhesus monkeys. The potential clinical or therapeutic value of delta agonists may reside with their interaction with mu opioid receptor systems, because delta opioid agonists are similar to mu opioids on measures of respiration and complex behavioral processes but devoid of analgesic effects in rhesus monkeys.