Effects of butorphanol on morphine-induced itch and analgesia in primates

Abstract

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.

Fig. 1

Comparison of behavioral effects produced by subcutaneous administration of butorphanol and morphine. (A) Dose–response curve for itch/scratching responses. (B) Dose–response curve for antinociception against 50°C water. Behavioral responses were determined using a cumulative dosing procedure. Each value represents mean ± SEM (n = 6). Symbols represent different dosing conditions for the same monkeys. * Significant difference from the vehicle condition (P < 0.05).

Fig. 2

Effects of κ- and μ-opioid receptor antagonists on systemic butorphanol-induced behavioral effects in monkeys. A κ-opioid receptor antagonist (5′-guanidinylnaltrindole [GNTI], 1 mg/kg) or a μ-opioid receptor antagonist (clocinnamox [CCAM], 0.1 mg/kg) was administered intramuscularly 1 day before redetermination of the dose–response curve of subcutaneous butorphanol. (A) Dose–response curve for itch/scratching responses. (B) Dose–response curve for antinociception against 50°C water. Each value represents mean ± SEM (n = 6). Symbols represent pretreatment with different antagonists for the same monkeys. * Significant difference from the vehicle pretreatment condition (P < 0.05).

Fig. 3

Effects of butorphanol pretreatment on systemic morphine dose–response curves for scratching and antinociception. Butorphanol (mg/kg) was administered subcutaneously 15 min before the injection of the first dose of subcutaneous morphine. A and B: Effects of butorphanol on morphine-induced scratching responses. C and D: Effects of butorphanol on morphine-induced antinociception against 50°C water. E and F: Effects of butorphanol combined with morphine on the sedation. Each value represents mean ± SEM (n = 6). Symbols represent different experimental conditions for the same monkeys. * Significant difference from the vehicle pretreatment condition, subcutaneous morphine alone (P < 0.05). See figures 1 and 2 for other details.

Fig. 4

Effects of butorphanol intervention on intrathecal morphine–induced scratching and antinociception. Butorphanol (mg/kg) was administered subcutaneously 45 min after intrathecal administration of 32 μg morphine. A, B, and C represent effects of butorphanol on morphine-induced scratching, antinociception, and sedation, respectively. Each value represents mean ± SEM (n = 6). Symbols represent different experimental conditions for the same monkeys. * Significant difference from the vehicle condition between time points 1.5 and 2.5 h (P < 0.05). See Results section for other details.

Fig. 5

Antagonist effect of 5′-guanidinylnaltrindole (GNTI) on the actions of butorphanol against intrathecal morphine–induced scratching (A) and antinociception (B). Butorphanol (0.032 mg/kg) was administered subcutaneously 45 min after 32 μg intrathecal morphine. Filled symbols represent the effect of GNTI (1 mg/kg) 1-day pretreatment (PT) on the actions of subcutaneous butorphanol against intrathecal morphine. Each value represents mean ± SEM (n = 6). * Significant difference between experimental conditions, (GNTI + [morphine + butorphanol]) and (morphine + butorphanol). # Significant difference between experimental conditions, (GNTI + [morphine + butorphanol]) and (morphine alone). The effect of GNTI 14-day pretreatment was not shown for the sake of clarity because its effect was similar to that of (morphine + butorphanol). See Results section for other details.

Fig. 6

Antagonist effect of nor-binaltorphimine (nor-BNI) on the actions of butorphanol against intrathecal morphine–induced scratching (A) and antinociception (B). Butorphanol (0.032 mg/kg) was administered subcutaneously 45 min after 32 μg intrathecal morphine. Filled symbols represent the effects of nor-BNI (3.2 mg/kg) 1- or 14-day pretreatment (PT) on the actions of subcutaneous butorphanol against intrathecal morphine. Each value represents mean ± SEM (n = 6). * Significant difference between experimental conditions, (nor-BNI + [morphine + butorphanol]) and (morphine + butorphanol). # Significant difference between experimental conditions, (nor-BNI + [morphine + butorphanol]) and (morphine alone). The effect of nor-BNI 28-day pretreatment was not shown for the sake of clarity because its effect was similar to that of (morphine + butorphanol). See Results section for other details.