Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord
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REVIEW
Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord David I Hughes 1
&
Andrew J Todd 1
Accepted: 22 September 2020 # The Author(s) 2020
Abstract Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontaneous. Given that one in three chronic pain patients do not respond to the treatments currently available, the need for more effective analgesics is evident. Two principal obstacles to the development of novel analgesic therapies are our limited understanding of how neuronal circuits that comprise these pain pathways transmit and modulate sensory information under normal circumstances and how these circuits change under pathological conditions leading to chronic pain states. In this review, we focus on the role of inhibitory interneurons in setting pain thresholds and, in particular, how disinhibition in the spinal dorsal horn can lead to aberrant sensory processing associated with chronic pain states. Key Words GABA . glycine . spinal cord . chronic pain . allodynia.
Inhibitory Interneurons in the Spinal Dorsal Horn The dorsal horn of the spinal cord is the principal termination site of primary afferents that innervate the skin and deeper tissues of the trunk and limbs and is composed of several distinct classes of neurons. These afferent fibers engage discrete, modality-specific circuits comprised of spinal interneurons that play important roles in modulating and gating afferent input, and projection neurons that relay the processed information to higher brain centers [1]. Nociceptive afferents of various types terminate primarily in laminae I, II, and V, with the central terminals of thinly myelinated Aδ fibers terminating in lamina I and V [2], peptidergic C-fibers arborizing in Aligning New Approaches to Accelerate the Development of Analgesic Therapies * David I Hughes [email protected] 1
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland
lamina I and the outer part of lamina II (IIo), and nonpeptidergic C-fibers that express the mas-related G proteincoupled receptor MrgD (CMrgD afferents) and bind isolectin B4 (IB4) terminating in mid-lamina II [3, 4]. Low-threshold mechanoreceptor afferents (LTMRs) terminate in deeper dorsal horn laminae, with unmyelinated C-LTMRs arborizing in the ventral part of lamina IIi, Aδ-LTMRs in lamina IIi and III, and Aβ-LTMRs in lamina IIi and III [5]. To allow the barrage to sensory input into the spinal cord to be perceived in context, afferent input into the central nervous system must be gated and prioritized—this p
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