Diffuse noxious inhibitory controls in chronic joint inflammatory Pain: Study of the descending serotonergic modulation mediated through 5HT3 receptors

Raquel Pereira-Silva; Paula Serrão; Fani Lourença Neto; Isabel Martins

doi:10.1016/j.ynpai.2023.100123

Diffuse noxious inhibitory controls in chronic joint inflammatory Pain: Study of the descending serotonergic modulation mediated through 5HT3 receptors

Neurobiol Pain. 2023 Mar 1:13:100123. doi: 10.1016/j.ynpai.2023.100123. eCollection 2023 Jan-Jul.

Authors

Raquel Pereira-Silva^{1

2

3}, Paula Serrão^{4

5}, Fani Lourença Neto^{1

2

3}, Isabel Martins^{1

2

3}

Affiliations

¹ Instituto de Investigação e Inovação em Saúde da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200 393 Porto, Portugal.
² Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal.
³ Departamento de Biomedicina - Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal.
⁴ Departamento de Biomedicina - Unidade de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal.
⁵ MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto. Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal.

Abstract

The loss of diffuse noxious inhibitory controls (DNIC) is recognized as a predictor of chronic pain. Mechanistically, DNIC produces analgesia by a heterotopically applied conditioning-noxious stimulus (CS) and yet underexplored descending modulatory inputs. Here, we aimed at studying DNIC in monoarthritis (MA) by exploring the spinal component of the descending serotonergic system, specifically 5-hydroxytryptamine 3 receptors (5-HT3R). MA was induced in male Wistar rats by tibiotarsal injection of complete Freund's adjuvant. Mechanical hyperalgesia and DNIC were assessed weekly by the Randall-Selitto test. Immunohistochemistry was used to quantify spinal 5-HT3R, and tryptophan hydroxylase (TPH) colocalization with phosphorylated extracellular signal-regulated protein kinases 1/2 at the rostroventromedial medulla (RVM). Spinal serotonin (5-HT) was quantified by HPLC. The effects of intrathecal ondansetron, a 5-HT3R antagonist, were assessed on mechanical hyperalgesia and DNIC. MA resulted in a prolonged steady-state mechanical hyperalgesia. In contrast, DNIC peaked after 28 days, decreasing afterwards until extinction at 42 days. At this later timepoint, MA rats showed increased: (i) spinal 5-HT3R and 5-HT levels, (ii) neuronal serotonergic activation and TPH expression at the RVM. Ondansetron reversed mechanical hyperalgesia and restored DNIC, regardless of being administered before or after CS. However, data variability was higher upon administration before CS in MA-animals. Prolonged MA upregulates the descending serotonergic modulation, which simultaneously results in increased nociception and DNIC extinction, through 5-HT3R. Our data suggest a role for spinal 5-HT3R in the top-down modulation of DNIC. Additionally, these receptors may also be involved in the bottom-up circuitry implicated in the trigger of DNIC.

Keywords: Chronic inflammatory joint pain; Descending serotonergic pain modulation; Diffuse noxious inhibitory controls; Rostral ventromedial medulla; Spinal 5-hydroxytryptamine 3 receptors.