Translational value of non-human primates in opioid research

Ding, Huiping; Ko, Mei‐Chuan

doi:10.1016/j.expneurol.2021.113602

Cited by 12 publications

(6 citation statements)

References 162 publications

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“…12,15 The antagonist studies revealed a larger μ receptor contribution than the nociceptin receptor, and no involvement of δ and κ receptors in cebranopadol-induced antinociception in the nonhuman primate model of acute pain. δ and κ Receptor agonists are known to cause convulsions or sedation in nonhuman primates 24 ; therefore, the absence of convulsive and sedative behaviors after cebranopadol administration in our study is consistent with the lack of involvement of δ and κ receptors. The nociceptin receptor antagonist had a weak influence on the antinociceptive effect of cebranopadol.…”

Section: Cebranopadol In Nonhuman Primatessupporting

confidence: 88%

“…Given the species differences in the functional and pharmacologic profiles of nociceptin and μ receptor activation between rodents and nonhuman primates and the practicality of simulating the side effect profiles of μ receptor agonists in nonhuman primates, 5,24,25 we used nonhuman primate models in this study to compare the functional profiles of cebranopadol with μ receptor agonists fentanyl and morphine in four aspects: (1) antinociceptive potency; (2) reinforcing effects and strength; (3) respiratory depressant effects; and (4) pruritic effects.…”

Section: Functional Profile Of Systemic and Intrathecal Cebranopadol ...mentioning

confidence: 99%

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Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Ding¹,

Trapella²,

Kiguchi³

et al. 2021

Anesthesiology

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Background Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose–response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Section: Cebranopadol In Nonhuman Primatessupporting

confidence: 88%

Section: Functional Profile Of Systemic and Intrathecal Cebranopadol ...mentioning

confidence: 99%

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Ding¹,

Trapella²,

Kiguchi³

et al. 2021

Anesthesiology

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“…BU08028 had sex‐dependent beneficial and detrimental effects on some measures of heroin relapse and sex‐independent null effects on other relapse measures and heroin choice. To the extent that our rat models of relapse and choice predict medication efficacy in humans (Banks & Negus, 2017; Epstein et al, 2006; Venniro et al, 2020), our results do not support the suggestion, derived from non‐human primate studies (Ding & Ko, 2021), that mixed NOP/ μ receptor partial agonists should be considered for the treatment of opioid addiction in humans.…”

Section: Discussioncontrasting

confidence: 69%

“…do not support the suggestion, derived from non-human primate studies (Ding & Ko, 2021), that mixed NOP/ μ receptor partial agonists should be considered for the treatment of opioid addiction in humans.…”

Section: Dissociable Effects Of Bu08028 On Different Relapse-related ...mentioning

confidence: 56%

“…Therefore, there is an unmet need to advance novel medications for the treatment of opioid use and relapse. In this regard, one class of drugs that has recently received considerable attention are those that act as partial agonists at both the μ opioid receptor and the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor (Ding & Ko, 2021; Zaveri, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Bossert

Townsend

Altidor

et al. 2021

British J Pharmacology

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Background and Purpose Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse‐related measures and heroin versus food choice. Experimental Approach For relapse assessment, we trained male and female rats to self‐administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin‐seeking in a non‐drug Context B, (2) extinction responding reinforced by heroin‐associated discrete cues in Context B, (3) reinstatement of heroin‐seeking induced by re‐exposure to Context A and (4) re‐acquisition of heroin self‐administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re‐acquisition of heroin self‐administration selectively in females. Chronic BU08028 had minimal effects on context‐induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications Chronic BU08028 delivery had both beneficial and detrimental, sex‐dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.

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