Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys.

G-protein-biased mu-opioid receptor (GPB-MOR) agonists are an emerging class of compounds being evaluated as candidate analgesics and agonist medications for opioid use disorder. Most of the basic pharmacology of GPB-MOR agonists has been conducted in rodents and much less is known how the basic behavioral pharmacology of these compounds translates to nonhuman primates. The present study determined the antinociceptive potency and time course of three putative GPB-MOR agonists: (+)-oliceridine (i.e. TRV130), SR14968, and SR17018 in male rhesus monkeys (n = 3). In addition, the respiratory effects of these compounds were also indirectly determined using a pulse oximeter to measure percent peripheral oxygen saturation (%SpO2). The largest intramuscular oliceridine dose (3.2 mg/kg) produced significant antinociception at 50°C, but not 54°C, and peak effects were between 10 and 30 min. Oliceridine also decreased SpO2 below the 90% threshold that would be clinically categorized as hypoxia in two out of three monkeys. The largest intramuscular SR14968 dose (0.32 mg/kg) produced 100% MPE at 50°C, but not 54°C, in two out of three monkeys, and peak effects were between 30 and 100 min. The largest intravenous SR17018 dose (1 mg/kg) produced 100% MPE at 50°C, but not 54°C, in the same two out of three monkeys, and peak effects were between 30 and 100 min. Solubility limitations for both SR14968 and SR17018 impaired our ability to determine in-vivo potency and effectiveness on antinociceptive and %SpO2 measures for these two compounds.

Role of mu-opioid agonist efficacy on antinociceptive interactions between mu agonists and the nociceptin opioid peptide agonist Ro 64-6198 in rhesus monkeys.

Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14ß-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n = 3-4) and schedule-controlled responding (n = 3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32 mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys.

Receptor theory predicts that fixed-proportion mixtures of a competitive, reversible agonist (e.g., fentanyl) and antagonist (e.g., naltrexone) at a common receptor [e.g., mu-opioid receptors (MORs)] will result in antagonist proportion-dependent decreases in apparent efficacy of the agonist/antagonist mixtures and downward shifts in mixture dose-effect functions. The present study tested this hypothesis by evaluating behavioral effects of fixed-proportion fentanyl/naltrexone mixtures in a warm-water tail-withdrawal procedure in rhesus monkeys (n = 4). Fentanyl (0.001-0.056 mg/kg) alone, naltrexone (0.032-1.0 mg/kg, i.m.) alone, and fixed-proportion mixtures of fentanyl/naltrexone (1:0.025, 1:0.074, and 1:0.22) were administered in a cumulative-dosing procedure, and the proportions were based on published fentanyl and naltrexone Kd values at MOR in monkey brain. Fentanyl alone produced dose-dependent antinociception at both 50 and 54°C thermal intensities. Up to the largest dose tested, naltrexone alone did not alter nociception. Consistent with receptor theory predictions, naltrexone produced a proportion-dependent decrease in the effectiveness of fentanyl/naltrexone mixtures to produce antinociception. The maximum effects of fentanyl, naltrexone, and each mixture were also used to generate an efficacy-effect scale for antinociception at each temperature, and this scale was evaluated for its utility in quantifying 1) efficacy requirements for antinociception at 50 and 54°C and 2) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPγS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14ß-dihyroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamindo]morphine, nalbuphine, buprenorphine, oxycodone, morphine, and methadone). These results suggest that fixed-proportion agonist/antagonist mixtures may offer a useful strategy to manipulate apparent drug efficacy for basic research or therapeutic purposes.

Additive and subadditive antiallodynic interactions between µ-opioid agonists and N-methyl D-aspartate antagonists in male rhesus monkeys.

µ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of µ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of µ-agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (-)-nalbuphine, and (-)-oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of µ-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to µ-opioid agonists for thermal allodynic pain states.