Effects of butorphanol on morphine-induced itch and analgesia in primates.
BACKGROUND
Butorphanol is an opioid analgesic with partial agonist actions at micro- and kappa-opioid receptors (MOR and KOR). Previous studies have demonstrated that both MOR antagonists and KOR agonists are effective in alleviating intrathecal morphine-induced itch in primates. The aim of the study was to investigate the effectiveness of butorphanol as an antipruritic and to elucidate the receptor mechanisms underlying butorphanol's antipruritic effect in primates.


METHODS
Adult rhesus monkeys were used in the behavioral assays for measuring itch/scratching and analgesia. The dose-response curves of butorphanol were studied using selective MOR and KOR antagonists. In addition, the effect of butorphanol as an antipruritic was studied on subcutaneous and intrathecal morphine-induced itch and analgesia. KOR-selective antagonists were further used to compare the degrees of MOR and KOR activation underlying the antipruritic effect of butorphanol.


RESULTS
Butorphanol alone produced analgesia with slight itch responses, and both effects were blocked by a MOR antagonist, clocinnamox (0.1 mg/kg). In contrast, a KOR antagonist, 5'-guanidinylnaltrindole (1 mg/kg), increased butorphanol-elicited itch. Systemic butorphanol (0.0032-0.032 mg/kg) dose-dependently attenuated systemic or intrathecal morphine-induced itch. In addition, butorphanol either potentiated or maintained morphine-induced analgesia without producing sedation. KOR-selective antagonists, 5'-guanidinylnaltrindole (1 mg/kg) and nor-binaltorphimine (3.2 mg/kg), only partially reversed the antipruritic effect of butorphanol with different durations of KOR antagonism.


CONCLUSIONS
Butorphanol is effective in attenuating systemic or spinal morphine-induced itch without reducing morphine analgesia. This study provides functional evidence that both partial MOR and KOR agonist actions contribute to the effectiveness of butorphanol as an antipruritic in primates.
Lee
Heeseung
H
Department of Anesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea.
Naughton
Norah N
NN
Woods
James H
JH
Ko
Mei-Chuan
MC
D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002077:Butorphanol / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D011537:Pruritus / Q000139:chemically induced* / Q000188:drug therapy*; D011957:Receptors, Opioid / Q000187:drug effects; D013997:Time Factors
D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D009020:Morphine; D002077:Butorphanol