Descending control of nociception: Specificity, recruitment and plasticity

Abstract

The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.

Fig. 1. Schematic illustrates main topics of this review

midline PAG-RVM system, which exerts bidirectional control over dorsal horn nociceptive processing, and the DRt and VLM in the caudal medulla. DRt is thought to be facilitating, and VLM primarily inhibitory, although it may, like the RVM, have both an inhibitory and facilitatory influence. The PAG especially, but also the RVM, DRt and VLM (not shown) receive important direct and indirect inputs from limbic forebrain areas including anterior cingulate cortex (ACC), amygdala (AMY), dorsomedial nucleus of the hypothalamus (DMH), and medial prefrontal cortex (MPC).

Fig. 2. A simplified model to explain how descending control from the PAG, which targets different populations of superficial dorsal horn neurons, could produce an inhibition of deep dorsal horn neurons that is proportional to their C-fiber input, but a facilitation of other neurons with weak or no C-fiber input

Solid lines represent direct (monosynaptic) connections, dotted lines represent indirect (polysynaptic) connections between neurons; open triangles/black lines are excitatory synapses and gray lines/filled triangles are inhibitory connections. The PAG inhibits superficial dorsal horn neurons that relay information carried by C-fibers to the deep dorsal horn. The net inhibitory or facilitatory effect of PAG stimulation is also a function of reciprocal inhibition between C+ve and C-ve neurons at the segmental level. C+ve: C-fiber input positive, C-ve: C-fiber input negative.