LAUSR

Descending pain inhibition is a key component of physiological and pathological pain processing. Various neurotransmitter systems underlie different descending pain inhibitory pathways. Their anatomical and functional details have recently been revealed; thanks to new techniques that allow circuit tracing (virus-based tracing) and circuit manipulation (chemogenetics and optogenetics) with unprecedented precision. Translation, however, remains challenging because the application of optogenetics and chemogenetics in humans faces substantial hurdles and because the more traditional pharmacological approaches would require that descending pain inhibition in humans and experimental animals involves the same transmitters and receptors. Prime examples of experimental paradigms assessing descending pain modulation in humans and animals are conditioned pain modulation (CPM) and diffuse noxious inhibitory controls (DNIC), respectively. Diffuse noxious inhibitory controls are measured as the inhibition of second-order wide dynamic range neurons (WDRs) by the application of a noxious stimulus outside the receptive field of the recorded neuron. In CPM paradigms, this “pain-inhibits-pain” effect is assessed via the modulation of the perceived pain intensity caused by a noxious test stimulus by another noxious heterotopically applied “conditioning” stimulus. Yet, few CPM studies offer mechanistic insights, making direct comparisons between DNIC and CPM mechanisms challenging. This topical review outlines preclinical evidence how various neurotransmitter systems contribute to descending pain inhibition and highlights those systems likely involved in DNIC. Indications for similar neurochemical processes in human CPM studies are discussed and synthesized with preclinical evidence, outlining gaps to be addressed by future studies.