A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia

Abstract

Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated Aβ-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory Aβ-fiber inputs onto PKCγ + neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents Aβ input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by Aβ-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.

Glycine transport inhibitors for the treatment of pain

“…In trigeminal mechanical allodynia induced by strychnine microinfusion, glycine signalling is decreased through a local PKCγ-mediated excitatory NMDA circuit [26]. This was further studied in lumbar dorsal horn neurons in a neuropathic pain model [14], which revealed suppression of a feed-forward glycinergic circuit that gates mechanical allodynia (Figure 2). Additionally, in neuropathic pain, a shift in the anion gradient develops exclusively in dorsal horn lamina I pain transmission neurons [27].…”

“…These glycinergic neurons contribute to inhibition of nociceptive signalling and have important roles in segregating nociceptive and non-noxious information pathways [1,11] (see Figure 2). Dysfunctions of glycinergic systems, together with GABAergic systems [14][15][16][17][18][19], contribute to neuropathic and inflammatory pain.…”

“…As outlined in Figure 2, lamina III glycinergic neurons prevent non-nociceptive, mechanical information from reaching pain projection neurons in lamina I of the dorsal horn [14,18]. Impairment of this inhibitory mechanism has been directly demonstrated in neuropathic pain models [14], which is likely to contribute to mechanical hyperalgesia and allodynia, and perhaps spontaneous pain states [14,18]. The ability of GlyT2 inhibitors to reverse mechanical allodynia is likely to be due, at least in part, to restoration of these inhibitory mechanisms.…”

“…In normal physiological states, excitatory Aβ (light touch) sensory inputs converge onto excitatory interneurons (green cells; E, some of which are PKCγ-positive) in lamina II of superficial dorsal horn, as well as glycinergic neurons in lamina III (blue cells; Gly) [1,11,14,19]. Coincident activation of these glycinergic interneurons produces strong feed-forward inhibition of lamina II excitatory interneurons (green; E) that prevents non-noxious sensory information from invading pain transmission neurons in lamina I (red cell; NK1 receptor positive) [14,19]. This feed-forward inhibition is suppressed following peripheral nerve injury, or pharmacological glycine receptor inhibition, allowing non-noxious information to invade lamina I neurons [14,[16][17][18][19].…”

“…Coincident activation of these glycinergic interneurons produces strong feed-forward inhibition of lamina II excitatory interneurons (green; E) that prevents non-noxious sensory information from invading pain transmission neurons in lamina I (red cell; NK1 receptor positive) [14,19]. This feed-forward inhibition is suppressed following peripheral nerve injury, or pharmacological glycine receptor inhibition, allowing non-noxious information to invade lamina I neurons [14,[16][17][18][19]. Thus non-noxious light touch information is perceived as painful (allodynia).…”