Diffuse Noxious Inhibitory Controls in Chronic Pain States: Insights from Pre-Clinical Studies

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement of several neurochemical systems in DNIC/CPM and point to a major contribution of the noradrenergic, serotonergic, and opioidergic systems. Here, we thoroughly review the latest data on the monoaminergic and opioidergic studies, focusing particularly on pre-clinical models of chronic pain. We also conduct an in-depth analysis of these systems by integrating the available data with the descending pain modulatory circuits and the neurochemical systems therein to bring light to the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic effects but also hyperalgesic effects. This duality might be explained by the underlying circuitry and the receptor subtypes involved therein. Acknowledging this duality might contribute to validating the prognostic nature of the paradigm. Additionally, DNIC/CPM may serve as a robust paradigm with predictive value for guiding pain treatment through more effective targeting of descending pain modulation.