Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states

Ryan Patel,Anthony H Dickenson

doi:10.1016/j.neuropharm.2018.09.028

Abstract

Descending brainstem control of spinal nociceptive processing permits a dynamic and adaptive modulation of ascending sensory information. Chronic pain states are frequently associated with enhanced descending excitatory drive mediated predominantly through serotonergic neurones in the rostral ventromedial medulla. In this study, we examine the roles of spinal 5-HT2A and 5-HT3 receptors in modulating ascending sensory output in normal and neuropathic states. In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus. In sham rats, block of spinal 5-HT3Rs with ondansetron revealed tonic facilitation of noxious punctate mechanical stimulation, whereas blocking 5-HT2ARs with ketanserin had minimal effect on neuronal responses to evoked stimuli. The inhibitory profiles of both drugs were altered in SNL rats; ondansetron additionally inhibited neuronal responses to lower intensity punctate mechanical stimuli and noxious heat evoked responses, whereas ketanserin inhibited innocuous and noxious evaporative cooling evoked responses. Neither drug had any effect on dynamic brush evoked responses nor on spontaneous firing rates in both sham and SNL rats. These data identify novel modality and intensity selective facilitatory roles of spinal 5-HT2A and 5-HT3 receptors on sensory neuronal processing within the spinothalamic-somatosensory cortical pathway.

Highlights

Brainstem nuclei and higher brain centres can exert powerful modulation of nociceptive processing at the spinal level
We examine the roles of spinal 5-HT2A and 5-HT3 receptors in modulating ascending sensory output in normal and neuropathic states
In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus

Summary

Introduction

Brainstem nuclei and higher brain centres can exert powerful modulation of nociceptive processing at the spinal level This bi-directional control serves to amplify or suppress sensory transmission depending on context, expectation and emotional state. Descending modulation is largely orchestrated via the periaqueductal grey (PAG), locus coeruleus and rostral ventromedial medulla (RVM) (Ossipov et al, 2014), cortical regions such as the cingulate can exert direct facilitatory influences on spinal excitability (Chen et al, 2018), or indirectly via cortical-sub-cortical networks engaging descending brainstem pathways (Tan et al, 2017). Neurones within the RVM display distinct firing patterns in response to noxious somatic stimulation; quiescent ON-cells begin firing and are considered to mediate descending facilitation, whereas tonically active OFF-cells

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