Mu/kappa opioid interactions in rhesus monkeys: Implications for analgesia and abuse liability.

Abstract

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1 and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50°C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug selfadministration, rhesus monkeys responded for i.v. drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in both rates of fentanyl selfadministration and behavioral economic measures of the reinforcing efficacy of fentanyl. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Taken together, these ICSS effects with kappa agonists are consistent with the lack of evidence for reinforcing effects by kappa agonists in drug self-administration studies (Tang and Collins, 1985;Negus et al, 2008).…”

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

“…First, our previous study examined the effects of a single clomipramine dose administered as a pretreatment to multiple mu agonist doses. However, drug interactions can also be profitably studied by using fixed-proportions drug mixtures (Tallarida, 2000;Stevenson et al, 2003;Negus et al, 2008Negus et al, , 2009, and clinically available drug-combination products typically exist as fixed-proportion mixtures. Therefore, the present study examined effects of clomipramine administered in fixed proportions with the low-efficacy mu agonist nalbuphine, the moderate-efficacy mu agonist morphine, and the high-efficacy mu agonist methadone.…”

“…Second, the selectivity of clomipramine-mu agonist interactions for antinociception versus other effects is unknown. Insofar as motor impairment and nonspecific behavioral suppression may confound measures of thermal nociception, we therefore determined clomipramine-mu agonist interactions in an assay of schedule-controlled responding for comparison with antinociceptive interactions (Stevenson et al, 2003;Negus et al, 2008Negus et al, , 2009. Finally, to assess the generality of antinociceptive interactions to a model of inflammatory pain, clomipramine-nalbuphine interactions were also examined in an assay of capsaicin-induced thermal allodynia (Negus et al, 1993;Butelman et al, 2004;Do Carmo et al, 2008).…”

Sélectivité fonctionnelle des ligands des récepteurs opiacés

“…Cet article propose un tour d'horizon des travaux qui mettent en évi-dence la sélectivité fonctionnelle des ligands des récepteurs opiacés μ et  et expose deux hypothèses concernant le type de sélectivité fonctionnelle à cibler pour réduire le développement de tolérance analgésique. < [10], mais les proprié-tés psychomimétiques de ces agonistes [12], le développement de tolérance [13] ainsi que leurs effets dysphoriques et anxiogènes [14] limitent leur utilisation clinique. Enfin, les agonistes du DOR produisent certes moins de dépression respiratoire [15], de constipation [16] et de dépendance physique [17] que les agonistes du MOR, mais il a été démontré dans des modèles animaux de douleur chronique et aiguë qu'ils entraînent une tolérance à l'analgésie [11,18,19].…”

“…Les agonistes des récepteurs opiacés sont les analgésiques les plus efficaces actuellement disponibles. L'activation des trois sous-types conduit à des effets antinociceptifs, mais les opiacés généralement utilisés dans le traitement de la douleur (par exemple la morphine, l'hydromorphone, le fentanyl et l'oxycodone) agissent de façon pré-dominante sur le MOR, dont l'activation est indissociable d'effets indésirables tels que la constipation, la dépression respiratoire, la tolérance, la dépendance physique ainsi que les risques d'abus [9][10][11]. L'analgésie induite par les agonistes du KOR est associée à un potentiel DOR pour différentes sous-unités G varie en fonction de l'agoniste utilisé, démontrant ainsi que le ligand peut déterminer le partenaire de signalisation du récepteur auquel il est lié.…”