Descending antinociception induced by secondary somatosensory cortex stimulation in experimental neuropathy: role of the medullospinal serotonergic pathway

Abstract

Stimulation of the secondary somatosensory cortex (S2) has attenuated pain in humans and inflammatory nociception in animals. Here we studied S2 stimulation-induced antinociception and its underlying mechanisms in an experimental animal model of neuropathy induced by spinal nerve ligation (SNL). Effect of S2 stimulation on heat-evoked limb withdrawal latency was assessed in lightly anesthetized rats that were divided into three groups based on prior surgery and monofilament testing before induction of anesthesia: ) sham-operated group and) hypersensitive and ) nonhypersensitive (mechanically) SNL groups. In a group of hypersensitive SNL animals, a 5-HT receptor agonist was microinjected into the rostroventromedial medulla (RVM) to assess whether autoinhibition of serotonergic cell bodies blocks antinociception. Additionally, effect of S2 stimulation on pronociceptive ON-cells and antinociceptive OFF-cells in the RVM or nociceptive spinal wide dynamic range (WDR) neurons were assessed in anesthetized hypersensitive SNL animals. S2 stimulation induced antinociception in hypersensitive but not in nonhypersensitive SNL or sham-operated animals. Antinociception was prevented by a 5-HT receptor agonist in the RVM. Antinociception was associated with decreased duration of heat-evoked response in RVM ON-cells. In spinal WDR neurons, heat-evoked discharge was delayed by S2 stimulation, and this antinociceptive effect was prevented by blocking spinal 5-HT receptors. The results indicate that S2 stimulation suppresses nociception in SNL animals if SNL is associated with tactile allodynia-like hypersensitivity. In hypersensitive SNL animals, S2 stimulation induces antinociception mediated by medullospinal serotonergic pathways acting on the spinal 5-HT receptor, and partly through reduction of the RVM ON-cell discharge. Stimulation of S2 cortex, but not that of an adjacent cortical area, induced descending heat antinociception in rats with the spinal nerve ligation-induced model of neuropathy. Antinociception was bilateral, and it involved suppression of pronociceptive medullary cells and activation of serotonergic pathways that act on the spinal 5-HT receptor. S2 stimulation failed to induce descending antinociceptive effect in sham-operated controls or in nerve-ligated animals that had not developed mechanical hypersensitivity.

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…The somatosensory cortex is also involved in descending anti-nociception through reducing "on" cell discharge in the rostral ventromedial medulla (RVM) in a 5-HT 1A receptor-dependent fashion [108]. Interestingly, the administration of lidocaine to the RVM of SNL rats relieved allodynia in animals exhibiting pain, but precipitated allodynia in rats that had also undergone surgery, but did not exhibit pain-related behaviors [109], consistent with the bi-directional influence of the RVM in descending modulation.…”

The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System

“…The role of the 5-HT 1 receptor family except 5-HT 1E in pain has been long studied both together and separately. Among them, the 5-HT 1A receptor has been extensively investigated for its analgesic effect in multiple pain states, including neuropathic, inflammatory, and visceral pain [61][62][63]. The activation of the 5-HT 1A receptor inhibits adenylyl cyclase thus reducing the intracellular concentration of cyclic adenosine monophosphate (cAMP), and subsequently, K + channels open and Ca 2+ channels close, resulting in an inhibition of neuronal firing [64].…”

“…Glutamate administration in the central amygdala (CeA) produced bidirectional effects: increased hypersensitivity that was reversed by a spinal 5-HT 3 receptor antagonist and decreased hypersensitivity that was blocked by a spinal 5-HT 1A receptor antagonist, indicating a CeA-spinal descending pathway in pain modulation [71]. Somatosensory cortex (S2) stimulation caused antinociception in a spinal nerve ligation (SNL) model, and this effect was prevented by chemically activating 5-HT 1A receptors in the RVM or blocking 5-HT 1A receptors spinally, illustrating that S2 stimulation-induced analgesia in neuropathic pain is mediated by medullospinal descending serotonergic pathways [63]. In visceral pain, a clinical trial showed that tandospirone citrate (a partial agonist of 5-HT 1A receptors) had benefits in suppressing the abdominal symptoms of patients with functional dyspepsia [62], which was consistent with animal experiments [66].…”

5‐hydroxytryptamine in migraine: The puzzling role of ionotropic 5‐HT3 receptor in the context of established therapeutic effect of metabotropic 5‐HT1 subtypes

“…Together, the amygdala-periaqueductal grey-raphé axis can provide context-dependent control of pain integrating multiple inputs from the periphery (including nociceptors) and from other brain regions, including the somatosensory cortex 2 (SS2; Bourbia & Pertovaara, 2018). Electrical stimulation of the somatosensory cortex 1 (SS1) in rats with developed mechanical hypersensitivity attenuated pain involving spinal 5-HT 1A receptors (Sagalajev et al, 2017). Thus, there are multiple centres in the brain at different levels starting from the cortex that activate 5-HTcontaining processes culminating at the level of the brainstem and spinal cord.…”