Similar involvement of several brain areas in the antinociception of endogenous and exogenous opioids

The complete inhibitor of the enkephalin degrading enzymes, RE 101, N-{(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithio]-1-oxopropyl}-L-phenylalanine benzyl ester, which crosses the blood-brain barrier, induced antinociceptive effects similar to those of exogenous opiates. The almost complete absence of tolerance and dependence after chronic administration of RE 101 is therefore due to limited stimulation of opioid receptors by 'protected' endogenous enkephalins. In order to clarify the mechanisms involved in these response, we have investigated the participation of several brain structures in the antinociceptive effects induced by systemic administration of morphine or RE 101. Rats were implanted with bilateral cannulae into the ventro-basal thalamus, central amygdala and periaqueductal gray matter, or with a cannula into the raphe magnus nucleus. The antinociceptive responses induced by systemic morphine or RE 101 were measured by using the tail-electrical stimulation test, where three different thresholds were determined: motor response, vocalization and vocalization post-discharge. The ability of the opioid receptor antagonist methylnaloxonium to block these antinociceptive responses was evaluated after local injection into the different brain structures. The blockade of morphine- and RE 101-induced antinociception was similar, and was stronger when methylnaloxonium was injected into the periaqueductal gray matter and raphe magnus nucleus than when it was injected into the ventro-basal thalamus and amygdala. These results suggest that brain structures related to the control of pain seem to be the same for the antinociception induced by exogenous opiates and endogenous opioids.