Paradoxical hyperalgesia induced by μ-opioid receptor agonist endomorphin-2, but not endomorphin-1, microinjected into the centromedial amygdala of the rat

Abstract

The effects of endomorphin-2 or endomorphin-1 microinjected into the centromedial amygdala on the thermally-induced tail-flick response were studied in male CD rats. Microinjection of endomorphin-2 (8.7–35.0 nmol) given into the centromedial amygdala time- and dose-dependently decreased the tail-flick latencies. On the other hand, endomorphin-1 (8–32.6 nmol) given into the same site did not cause any change of the tail-flick latency. However, endomorphin-1 (32.6 nmol) or endomorphin-2 (35.0 nmol) given into the basolateral site of amygdala did not affect the tail-flick latency. Pretreatment with the antiserum against dynorphin A(1–17) (200 μg) significantly reversed the decrease of the tail-flick latency induced by endomorphin-2. The decrease of the tail-flick latency induced by endomorphin-2 was also blocked by the endomorphin-2 selective μ-opioid receptor antagonist 3-methoxynaltrexone (6.4 pmol) and by the N-methyl- d-aspartate (NMDA) receptor antagonist MK-801 (30 nmol), but not by the κ-opioid receptor antagonist nor-binaltorphimine (6.6 nmol). It is concluded that endomorphin-2, but not endomorphin-1, given into the centromedial amygdala stimulates a 3-methoxynaltrexone-sensitive μ-opioid receptor subtype to induce the release of dynorphin A(1–17), which then acts on the NMDA receptor, but not κ-opioid receptor for producing hyperalgesia. This conclusion is further supported by the additional findings that dynorphin A(1–17) (2.3 nmol) given into the centromedial amygdala also caused the decrease of the tail-flick latency, which was similarly blocked by the NMDA receptor antagonist MK-801 (30 nmol), but not κ-opioid receptor antagonist nor-binaltorphimine (6.6 nmol).