Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats

Abstract

Analgesia can be elicited following microinjections of morphine, μ-selective agonists and β-endorphin into the amygdala. These analgesic responses are mediated by opioid synapses in the periaqueductal gray (PAG) since general (naltrexone), μ ( β-funaltrexamine) and δ 2 (naltrindole isothiocyanate) opioid antagonists administered into the PAG significantly reduce both morphine and β-endorphin analgesia elicited from the amygdala. Supraspinal multiplicative opiate analgesic interactions have been observed between the PAG and rostroventromedial medulla (RVM), the PAG and locus coeruleus (LC), and the RVM and LC. The present study further examined the relationship between the amygdala and PAG in analgesic responsiveness by determining whether multiplicative analgesic interactions occur following paired administration of subthreshold doses of morphine into both structures, β-endorphin into both structures, morphine into one structure and β-endorphin into the other structure, or morphine and β-endorphin into one structure. Co-administration of subthreshold doses of morphine into both the amygdala and PAG results in a profound synergistic interaction on the jump test, but not the tail-flick test. Co-administration of subthreshold doses of β-endorphin into both structures also results in a profound test-specific synergistic interaction. In both cases, the magnitude of the interaction was similar regardless of the site receiving the fixed dose of the opioid, and the site receiving the variable dose of the opioid. Co-administration of β-endorphin (1 μg) into the amygdala and morphine (1 μg) into the PAG produced a potent interaction, but co-administration of morphine (1 μg) into the amygdala and β-endorphin (1 μg) into the PAG failed to produce interactive effects. Finally, co-administration of morphine (1 μg) and β-endorphin (1 μg) into either the amygdala alone or the PAG alone failed to produce an interaction, indicating the importance of regional opioid activation. These data are discussed in terms of the test-specificity of nociceptive processing in the amygdala, in terms of the multiple modulatory mechanisms mediating β-endorphin analgesia in the PAG, and in terms of whether the interactions are either mediated by anatomical connections between the amygdala and PAG or by mechanisms initiated by these two sites converging at another site or sites.