A systematic review on descending serotonergic projections and modulation of spinal nociception in chronic neuropathic pain and after spinal cord stimulation.

Lonne Heijmans,Martijn R Mons,Elbert A Joosten

doi:10.1177/17448069211043965

Lonne Heijmans, Martijn R Mons + Show 1 more

Open Access

https://doi.org/10.1177/17448069211043965

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Abstract

Chronic neuropathic pain is a debilitating ordeal for patients worldwide and pharmacological treatment efficacy is still limited. As many pharmacological interventions for neuropathic pain often fail, insights into the underlying mechanism and role of identified receptors is of utmost importance. An important target for improving treatment of neuropathic pain is the descending serotonergic system as these projections modulate nociceptive signaling in the dorsal horn. Also with use of last resort treatments like spinal cord stimulation (SCS), the descending serotonergic projections are known to be involved in the pain relieving effect. This systematic review summarizes the involvement of the serotonergic system on nociceptive modulation in the healthy adult rodent and the chronic neuropathic rodent and summarizes all available literature on the serotonergic system in the SCS-treated neuropathic rodent. Medline, Embase and Pubmed databases were used in the search for articles. Descending serotonergic modulation of nociceptive signaling in spinal dorsal horn in normal adult rat is mainly inhibitory and mediated by 5-HT1a, 5-HT1b, 5-HT2c, 5-HT3 and 5-HT4 receptors. Upon injury and in the neuropathic rat, this descending serotonergic modulation becomes facilitatory via activation of the 5-HT2a, 5-HT2b and 5-HT3 receptors. Analgesia due to neuromodulatory intervention like SCS restores the inhibitory function of the descending serotonergic system and involves 5-HT2, 5-HT3 and 5-HT4 receptors. The results of this systematic review provide insights and suggestions for further pharmacological and or neuromodulatory treatment of neuropathic pain based on targeting selected serotonergic receptors related to descending modulation of nociceptive signaling in spinal dorsal horn. With the novel developed SCS paradigms, the descending serotonergic system will be an important target for mechanism-based stimulation induced analgesia.

Highlights

Chronic neuropathic pain is an important worldwide problem that negatively impacts the quality of life of patients and imposes great socioeconomic costs.[1]
Facilitatory effects of descending serotonergic modulation on spinal nociception do exist in the healthy adult rodent and are mediated via activation of 5-HT1a, 5-HT2a/c and 5-HT3 receptors
The inhibitory modulation of 5-HT on nociceptive transmission in the dorsal horn (DH) of the healthy adult rodent is mediated via activation of 5-HT1a, 5HT1b, 5-HT2c, 5-HT3 and 5-HT4 receptors whereas facilitatory modulation is mediated by 5-HT1a receptors, 5-HT2a/c receptors and 5-HT3 receptors

Summary

Introduction

Chronic neuropathic pain is an important worldwide problem that negatively impacts the quality of life of patients and imposes great socioeconomic costs.[1]. As the main neurotransmitter involved in descending modulation of spinal nociceptive neurotransmission is serotonin, the present review focuses on serotonergic descending projections. All serotonergic innervation of the spinal cord originates from supraspinal sources. Whereas the dorsal raphe nucleus (DRN) provides mainly ascending projections to other brain structures, the nucleus raphe magnus (NRM) provides serotonergic input to the spinal DH.[4] Local 5-HT receptors mediate the net modulatory effect of 5-HT in the spinal DH (see Figure 1 and Table 1 for 5-HT receptor expression in spinal DH). Based on the receptors involved, the net effect of serotonergic descending modulation might be either inhibitory or facilitatory.[1,3,4,26]

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