Neural circuits for pain: Recent advances and current views

Abstract

The mammalian nervous system encodes many different forms of pain, from those that arise as a result of short-term low-grade interactions with noxious thermal, chemical, or mechanical sources to more serious forms of pain induced by trauma and disease. In this Review, we highlight recent advances in our understanding of the neural circuits that encode these types of pain. Promising therapeutic strategies based on recent advances are also highlighted.

Fig. 1.. Overall organization of somatosensory circuits.

Cutaneous sensory neurons (DRG) are activated by a variety of stimuli (bottom left) and project to the spinal cord dorsal horn (DH, middle left). In the DH (right), the central terminals of high-threshold nociceptors (HT) are located in the most superficial laminae [lamina I to the dorsal part of inner lamina II (II_id)] and lamina V. Low-threshold mechanoreceptors (LTMR) preferentially end in the deep dorsal horn [ventral part of inner lamina II (II_iv) to lamina V]. The spinal cord is divided into 10 laminae (the DH is I to VI) and is composed of numerous neuronal populations. Some identified populations are organized in longitudinal layers (only excitatory neurons are represented): neurons transiently expressing VGLUT3 (tVGLUT3, orange) in laminae III and IV, PKCγ (green) in lamina II_iv, calretinin (blue) in outer lamina II (II_o) and lamina II_id, vertical cells (yellow) in lamina II_o, and projection neurons (red) in laminae I, IV, and V. Projection neurons send information to the brainstem and thalamus and then on to several brain regions implicated in sensory-discriminative (upper left, light brown) and emotional (upper left, dark brown) sensory perception. ACC, anterior cingular cortex; SI (II), primary (secondary) somatosensory cortex; PAG, periaqueductal gray area; PB, parabrachial nucleus; AMY, amygdala; PFC, prefrontal cortex; BG, basal ganglia.

Fig. 2.. Organization of primary sensory neurons.

(A) The categories of myelinated and unmyelinated neurons and their respective functional roles are derived from large-scale transcriptional analyses, behavioral analyses, and the literature. (B) The locations of the central terminations of the primary sensory neuron categories are shown. The schematic is based on analyses of gene reporter mouse lines (PV, RET, TRKB, TH, MRGPRD, MRGPRA3, CGRP, and TRPM8) and immunohistological analyses (TRKA, TRPV1, TAC1). Myelinated neurons preferentially express neurofilament heavy chain (NEFH), and unmyelinated neurons preferentially express the sodium channels Nav1.8 and −1.9. Laminae are indicated on the left. RET, ret proto-oncogene; CALB1, calbindin 1; TAC1, tachykinin 1; SST, somatostatin; NPPB; natriuretic peptide type B.

Fig. 3.. Organization of the dorsal horn circuit for pain.

Peripheral nociceptors (blue) project onto excitatory interneurons in lamina II_o (central cell, dark gray; vertical cells, yellow) and onto neurokinin 1 receptor (NK1R) projection neurons (red) in lamina I. Nonpeptidergic afferents expressing MRGPRD (green) project to lamina II_id, including to excitatory vertical cells with ventrally directed elongated dendrites. Both primary afferents also contact inhibitory islet cells (horizontally elongated, pink). Stimulation of nociceptive afferents activates excitatory central cells, vertical cells, and NK1R projection neurons to mediate noxious pain. Inhibitory islet cells modulate this activity. Innocuous afferents (orange) project onto excitatory interneurons expressing tVGLUT3 in lamina III (brown), PKCγ in lamina II_iv (teal), and vertical cells in lamina II_o. Myelinated afferents also contact PV inhibitory interneurons in lamina III (radial, pink) and dynorphin inhibitory vertical cells in lamina II_o (vertical, pink). tVGLUT3 interneurons project onto excitatory vertical cell dendrites and intermediate excitatory interneurons in lamina III. Intermediate interneurons project onto PKCγ and calretinin excitatory interneurons in lamina II_iv. Inhibitory interneurons prevent A-fiber–mediated activation of the nociceptive network through feed-forward circuits that act on PKCγ interneurons, vertical cells, and NK1R projection neurons. After nerve injury, inhibition by PV and dynorphin interneurons is reduced, allowing A-fiber–mediated activation of a dorsally directed circuit that includes tVGLUT3 and PKCγ neurons. After inflammatory injury, reduction in a still-unknown mechanism of disinhibition allows A-fiber–mediated activation of a dorsally directed circuit that includes tVGLUT3 and lamina II_iv calretinin neurons.