Developments in Understanding Diffuse Noxious Inhibitory Controls: Pharmacological Evidence from Pre-Clinical Research

Abstract

Bulbospinal pathways regulate nociceptive processing, and inhibitory modulation of nociception can be achieved via the activity of diffuse noxious inhibitory controls (DNIC), a unique descending pathway activated upon application of a conditioning stimulus (CS). Numerous studies have investigated the effects of varied pharmacological systems on the expression status of a) DNIC (as measured in anaesthetised animals) and b) the descending control of nociception (DCN), a surrogate measure of DNIC-like effects in conscious animals. However, the complexity of the underlying circuitry that governs initiation of a top-down inhibitory response in reaction to a CS, coupled with the methodological limitations associated with using pharmacological tools for its study, has often obscured the exact role(s) of a given drug. In this literature review, we discuss the pharmacological manipulation interrogation strategies that have hitherto been used to examine the functionality of DNIC and DCN. Discreet administration of a substance in the spinal cord or brain is considered in the context of action on one of four hypothetical systems that underlie the functionality of DNIC/DCN, where interpreting the outcome is often complicated by overlapping qualities. Systemic pharmacological modulation of DNIC/DCN is also discussed despite the fact that the precise location of drug action(s) cannot be pinpointed. Chiefly, modulation of the noradrenergic, serotonergic and opioidergic transmission systems impacts DNIC/DCN in a manner that relates to drug class, route of administration and health/disease state implicated. The advent of increasingly sophisticated interrogation tools will expedite our full understanding of the circuitries that modulate naturally occurring pain-inhibiting pathways.

The Effect of Palmitoylethanolamide on Pain Intensity, Central and Peripheral Sensitization, and Pain Modulation in Healthy Volunteers—A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial

“…It is generally regarded as a marker of the effectiveness of the inherent pain inhibition ability. It is well-documented that modulation of the noradrenergic transmission system affects this endogenous pain inhibition [ 43 ]. Wind-up describes the enhanced pain response to a series of stimuli compared to a single stimulus [ 17 ].…”

The origin of diffuse noxious inhibitory controls

“…The functional expression of DNIC was previously recorded in anaesthetised 4,9,17 and wakeful animals 18 , or quantified according to markers of spinal activity 19,20 , reviewed in 21 . We examined DNIC expression in healthy rats under light isoflurane/N 2 O/O 2 anaesthesia (slight toe pinch reflex maintained, and heart rate between 350-400 bpm).…”

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

“…Kucharczyk et al summarized pharmacological manipulations of DNIC, supporting an impact of noradrenergic, serotonergic, and opioidergic systems on DNIC. 54 In contrast to findings from animal experiments, pharmacological CPM studies question a critical role of noradrenaline in CPM. Systemic manipulations of α2-, 4 , 27 , 67 α1-, 27 or β-adrenoceptors 73 did not affect CPM except the application of one particular selective α2-adrenoceptor agonist, ie, dexmedetomidine.…”