Abstract
Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.
Highlights
Mu-opioid receptor agonists are effective analgesics for the treatment of many types of pain, but their clinical use is limited by undesirable effects that include sedation, respiratory depression, constipation, and high abuse liability [1, 2]
Preclinical procedures have been developed to examine effects of opioids and other drugs on inflammation-associated allodynia [13], but interactions between delta and mu agonists in these clinically relevant procedures have not been evaluated. To address this knowledge gap, the present study evaluated interactions between the nonpeptidic delta agonist SNC80 and the mu-opioid agonists methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys
A higher dose of 5.6 mg/kg SNC80 produced modest antiallodynic effects in two monkeys (%MPE of 56.5 and 37.5%), but this dose produced a convulsion in a third monkey and was not tested further
Summary
Mu-opioid receptor agonists are effective analgesics for the treatment of many types of pain, but their clinical use is limited by undesirable effects that include sedation, respiratory depression, constipation, and high abuse liability [1, 2]. We and others have reported that delta opioid receptor agonists can selectively enhance the antinociceptive effects of mu agonists in assays of acute thermal pain while producing a lesser enhancement, no enhancement, or an attenuation of many undesirable effects of mu agonists [3,4,5,6,7]. Mu agonists may produce a reciprocal attenuation in undesirable effects produced by some delta agonists (e.g., convulsant activity [3]) These findings have been interpreted to suggest that mixtures of delta and mu agonists, or single compounds with mixed agonist activity at both delta and mu receptors, may be useful as alternatives to selective mu agonists for the treatment of pain. Responses to noxious stimuli are adaptive (e.g., by promoting movement of an affected limb away from a stimulus that could cause tissue damage), and opioids are used clinically to dampen these responses only as an adjunct to other drugs in the context of general or epidural anesthesia [8,9,10]
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