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

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.

Keywords: 5-HT; Serotonin; dorsal horn; neuropathic pain; nociception; spinal cord stimulation.

Figure 1.

Descending serotonergic fibers and 5-HT receptors in the dorsal horn nociceptive network of the adult rat. Dorsal horn nociceptive network: Nociceptive afferent fibers (thinly myelinated Aδ-fiber, unmyelinated C-fiber) terminate in the superficial layers (lamina I-II) of the DH where they either synapse on interneurons (lamina I-III) or NK1 receptor expressing projection neurons (lamina I). Neurotransmitters utilized by inhibitory interneurons (ININs) are γ-aminobutyric acid (GABA), glycine, or both. Excitatory interneurons (EXIN) utilize glutamate. The interneurons synapse on projection neurons either in lamina I (nociceptive specific) or in lamina III-V (wide dynamic range (WDR) neurons). WDR neurons have dendrites extending to the superficial lamina and thus synapses form nociceptive fibers, non-nociceptive fibers and interneurons. Non-noxious stimuli are transmitted by touch-responsive, myelinated Aβ fibers that terminate within lamina II-V and synapse onto the WDR and interneurons. Descending serotonergic neurons terminate most abundantly in the superficial laminae (I/II) but they also innervate deeper laminae (IV-VI).^,, Panel (b) depicts the enlarged inset of (a) and contains numbered pathways of 5-HT mediated nociceptive modulation: 1) Autoreceptor pathway; direct modulation of serotonin release through 5-HT1b autoreceptors on descending serotonergic terminals. 2) Projection neuron pathway; direct modulation through postsynaptic 5-HT3 and 5-HT5a expression on spinal projection neurons.^, 3) GABA ININ pathway; indirect modulation of projection neurons through 5-HT1a, 5-HT2a, 5-HT3 and 5-HT7 expressed on GABAergic ININs.^– 4) EXIN pathway; indirect modulation of projection neuron through 5-HT3 and 5-HT5a expression on EXINs.^, 5) Nociceptive afferent pathway; direct modulation of neurotransmitter release through expression of 5-HT1a, 5-HT1b, 5-HT2a, 5-HT3 and 5-HT7 on nociceptive afferent terminals.^,,,,– 6) Non-nociceptive afferents pathway; modulation via activation of GABAergic ININs by non-nociceptive afferents (Aβ fibers) according to the principle of the Gate-Control Theory.

Figure 2.

Schematic overview of the effect of descending serotonergic modulation on nociceptive transmission in the DH and the involved receptors in the healthy (a), neuropathic (b) and con-DC-SCS treated (c) rodent. Upon injury (b), 5-HT content in the DH is reduced and 5-HT1b and 5-HT4 receptors lose their inhibitory function. Con-DC-SCS (c) increases 5-HT release in DH. The – symbol means inhibitory mediation, the + symbol means facilitatory modulation.