Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord

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.

Keywords: GABA; allodynia.; chronic pain; glycine; spinal cord.

Fig. 1

Neurotransmitter heterogeneity of dorsal horn neurons. Fluorescent in situ hybridization labelling for VGLUT2 (magenta), GAD1 (green), and VGAT (white) shows excitatory interneurons (magenta) outnumber inhibitory interneurons (green and white, or white only) in laminae I–III. VGLUT2-expressing interneurons are common in laminae I–III. Inhibitory interneurons can be split into three subpopulations based on their neurotransmitter content: those that express GABA, those that express glycine, and those that express both GABA and glycine. In this figure, inhibitory interneurons that only express GABA, and those likely to co-express both GABA and glycine, show co-expression for both GAD1 and VGAT (green and white, respectively) and are common in laminae I–III, whereas cells that express only glycine are common in lamina IV (insets, yellow asterisks). AM Bell, AJ Todd, and DI Hughes, unpublished observations

Fig. 2

Neurochemical features of spinal inhibitory interneurons in laminae I and II. The estimated proportions of all inhibitory interneuron populations, as defined by their neurochemical profiles, are presented in the pie chart (modified from reference 10]. Four segments of this chart (parvalbumin, calretinin, neuropeptide Y, and galanin/dynorphin populations) correspond well with molecular clusters of inhibitory interneurons identified in single-cell RNA sequencing studies [12]. Taken together, these datasets provide a means of devising intersectional strategies to target subpopulations of interneuron with greater precision than possible previously

Fig. 3

Morphological and electrophysiological diversity within a neurochemically-defined population lamina II neurons. Targeted whole-cell patch-clamp recordings were carried out in spinal cord slices maintained in vitro from a transgenic mouse line where enhanced green fluorescent protein (eGFP) was expressed in calretinin (CR) interneurons. (a) The distribution of eGFP-labelled cells mirrors that of calretinin cells labelled using immunohistochemical approaches (CR-IR). (b) Five distinct action potential firing patterns were recorded in eGFP cells from lamina II. (c) The morphological features of recorded neurons were also determined, with five morphologically distinct groups being recorded, as well as a group of unclassified cells. The only correlation between morphology and firing pattern that could be established was that cells with tonic-firing discharge patterns were always islet cells (and all islet cells were tonic firing). Modified from reference

Fig. 4

The role of inhibitory parvalbumin-expressing interneurons in gating low-threshold tactile input. Under normal conditions, inhibitory parvalbumin-expressing interneurons (iPV, green) mediate presynaptic inhibition of A-LTMR input (red) and postsynaptic inhibition of both vertical cells (blue, V) and PKCγ-expressing interneurons (blue, PKCγ). Peripheral nerve injury results in a reduction of iPV excitability (iPV, grey), leading to spinal disinhibition. The loss of iPV-mediated inhibition allows A-LTMR input to activate vertical cells directly, and through a polysynaptic route incorporating PKCγ-expressing interneurons and transient central cells (TC, blue). Under these conditions, vertical cells can relay A-LTMR input activate projection neurons (PN, black) in lamina I and recruit pain circuits. Based on references , , ,