Negative modulation of spinal κ-opioid receptor-mediated antinociception by the µ-opioid receptor at selective doses of (-)-pentazocine

Abstract

The mixed-action κ-opioid receptor (KOR) agonist, pentazocine, binds to both KOR and the µ-opioid receptor (MOR). Racemic (±)-pentazocine and (-)-pentazocine, each administered systemically, have been shown to produce antinociception in various animal models. In contrast, racemic (±)-pentazocine failed to produce antinociception when administered intrathecally (i.t.). However, whether spinal activation of KOR and MOR by (-)-pentazocine produces antinociception and the relative contribution of KOR and MOR in mediating antinociception remain unknown. Hence, we investigated whether i.t. (-)-pentazocine produces dose-dependent modulation of acute thermal nociception. Drugs were administered intrathecally in Sprague-Dawley rats and tail flick latency was recorded. Pentazocine produced a significant antinociceptive effect that was mediated by KOR and/or MOR at differential doses. MOR blockade restored the antinociceptive effect of an ineffective dose and prolonged the duration of an effective dose of pentazocine. Hence, spinal KOR and MOR mediated the effect of pentazocine. This study provides evidence that spinal MOR negatively modulates the KOR-mediated antinociceptive effect of i.t. pentazocine.

Fig. 1

Intrathecal (−)-pentazocine produced dose-dependent antinociception. It significantly increased tail flick latency at 187.5 and 500 nmol (but not 125 and 250 nmol) doses in comparison to the vehicle-treated group between time points 5 and 50 min (all P<0.05).

Fig. 2

Spinal κ-opioid receptor (KOR) or μ-opioid receptor (MOR) mediated the antinociceptive effect of the low dose of pentazocine (187.5 nmol). The increase in tail flick latency by pentazocine was blocked by either nor-binaltorphimine (nor-BNI) or CTAP pretreatment throughout the duration of the experiment (all P<0.05 as compared with pentazocine only group) (Dotted line represents data replotted from Fig. 1 for instant comparison).

Fig. 3

Spinal μ-opioid receptor (MOR) negatively modulates the κ-opioid receptor (KOR)-mediated antinociceptive effect of pentazocine (250 nmol). CTAP, injected 5 min before pentazocine produced a significant increase in tail flick latency from 5 to 70 min in comparison to pentazocine only treated group (all P<0.05).

Fig. 4

μ-Opioid receptor (MOR) blockade prolonged the κ-opioid receptor (KOR)-mediated antinociceptive effect of 500 nmol pentazocine. The increase in tail flick latency produced by 500 nmol pentazocine was blocked by nor-binaltorphimine (nor-BNI); however, it was significantly prolonged by CTAP (time points 45−70 min; all P<0.05 as compared with pentazocine only group). Hence, the antinociceptive effect of 500 nmol pentazocine was mediated by KOR (Dotted line represents data replotted from Fig. 1 for instant comparison).