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Reinforcing, Antinociceptive, and Pruritic Effects of a G Protein‐Biased Mu Opioid Receptor Agonist, PZM21, in Primates
Author(s) -
Ding Huiping,
Kiguchi Norikazu,
Perrey David A.,
Nguyen Thuy,
Czoty Paul W.,
Zhang Yanan,
Ko MeiChuan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.683.3
Subject(s) - oxycodone , morphine , pharmacology , scratching , opioid , nociception , agonist , medicine , antagonist , analgesic , naltrexone , receptor , physics , acoustics
PZM21 is a newly discovered G protein‐biased mu opioid peptide (MOP) receptor agonist which exerts antinociceptive effects with fewer side effects in rodents. The aim of this study was to determine the functional profile of systemic and spinal delivery of PZM21 in non‐human primates. Effects of PZM21 were compared with those of MOP agonists, such as oxycodone and morphine, in a series of behavioral assays established in rhesus monkeys ( Macaca mutatta ). Following systemic administration, PZM21 (1–6 mg/kg) and oxycodone (0.1–0.6 mg/kg) dose‐dependently produced antinociceptive effects against an acute noxious stimulus. Similar to a prescription opioid oxycodone, PZM21 produced reinforcing effects in primates under fixed ratio (FR30) and progressive‐ratio (PR) schedules of intravenous drug self‐administration. Following intrathecal administration, PZM21 (0.03–0.3 mg) and morphine (0.003–0.03 mg) dose‐dependently produced antinociceptive effects. Although intrathecal PZM21 has a slower onset for eliciting itch scratching activities, intrathecal PZM21 (0.3 mg) and morphine (0.03 mg) both elicited robust scratching responses lasting for more than 5 hours. In addition, intrathecal PZM21 (0.03–0.3 mg) dose‐dependently attenuated capsaicin‐induced thermal allodynia. Anti‐allodynic effects of intrathecal PZM21 or morphine could be blocked by a MOP receptor antagonist, naltrexone. Taken together, these pharmacological studies in primates indicate that PZM21 displays similar functional efficacy as an analgesic like clinically used MOP agonists, oxycodone and morphine. Although structure‐based discovery of PZM21 opens a new, exciting chapter for G protein‐biased MOP agonists, the abuse potential and pruritic effect of PZM21 are not significantly different from those of clinically used opioid analgesics in primates. Support or Funding Information The US‐PHS grants DA044775, DA032568, and DA040693. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .