Parallel activation of multiple spinal opiate systems appears to mediate 'non-opiate' stress-induced analgesias

Pain is powerfully modulated by circuitries within the CNS. Two major types of pain inhibitory systems are commonly believed to exist: opiate (those that are blocked by systemic opiate antagonists and by systemic morphine tolerance) and non-opiate (those that are not). We used intrathecal delivery of mu, delta, and kappa opiate receptor antagonists to examine 3 well-accepted non-opiate stress-induced analgesias. Combined blockade of all 3 classes of opiate receptors antagonized all of the 'non-opiate' analgesias. Further experiments demonstrated that blocking mu and delta or mu and kappa was sufficient to abolish 'non-opiate' analgesias. Combined blockade of kappa and delta receptors was without effect. The clear conclusion is that all endogenous analgesia systems may in fact be opiate at the level of the spinal cord. Phenomena previously thought to be non-opiate appear to involve parallel activation of multiple spinal opiate processes. These findings suggest the need for a fundamental shift in conceptualizations regarding the organization and function of pain modulatory systems in particular, and opiate systems in general.