The role of 5-HT3 receptor inhibition in human pain modulation: a
double-blind crossover study

Bruno Vítor Martins Santiago; Bruno Augusto Parada; Thereza Christina Barja Fidalgo; Maud Parise; Nivaldo Ribeiro Villela

doi:10.63231/2595-0118.e20250034-en

Artigo Original

The role of 5-HT3 receptor inhibition in human pain modulation: a double-blind crossover study

O papel da inibição do receptor 5-HT3 na modulação da dor humana: um estudo duplo-cego cruzado

Bruno Vítor Martins Santiago; Bruno Augusto Parada; Thereza Christina Barja Fidalgo; Maud Parise; Nivaldo Ribeiro Villela

http://dx.doi.org/10.63231/2595-0118.e20250034-en BrJP, vol.8, e20250034, 2025

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Abstract

BACKGROUND AND OBJECTIVES: Dysregulation of descending pain modulation, characterized by an imbalance between facilitator and inhibitory pathways, plays a key role in the development and persistence of chronic pain. The conditioned pain modulation (CPM) paradigm is a well-established method for assessing descending pain control in humans. The 5-HT3 receptor (5-HT3R) is implicated in descending pain facilitation and has been associated with persistent pain states. This doubleblind, crossover physiological study aimed to investigate the effects of 5-HT3R inhibition with ondansetron on thermal and mechanical pain thresholds, assessed via quantitative sensory testing (QST), and on CPM (thermal stimulus) in healthy adults.

METHODS: Seventeen healthy volunteers underwent quantitative sensory testing (QST) and conditioned pain modulation (CPM) assessments at baseline and following an intravenous infusion of either 8 mg ondansetron or saline (NaCl 0.9%). One week later, they were reassessed using the opposite treatment following the same protocol. Changes in QST and CPM before and after each intervention were analyzed using paired t-tests or Wilcoxon matched-pairs signed-rank tests (significance threshold: p<0.05).

RESULTS: Ondansetron had no significant effect on QST measures, but significantly enhanced CPM compared to saline.

CONCLUSION: These findings suggest that 5-HT3R inhibition enhances endogenous pain inhibition without altering acute pain thresholds, highlighting its potential role in central pain modulation.

Keywords

Serotonin 5-HT3 receptor antagonists; Pain; Ondansetron; Central nervous system sensitization

Resumo

JUSTIFICATIVA E OBJETIVOS: A desregulação da modulação descendente da dor, caracterizada por um desequilíbrio entre as vias facilitatórias e inibitórias, desempenha um papel fundamental no desenvolvimento e na persistência da dor crônica. O paradigma da modulação condicionada da dor (CPM - conditioned pain modulation) é um método bem estabelecido para avaliar o controle descendente da dor em humanos. O receptor 5-HT3 (5-HT3R) está relacionado com a facilitação descendente da dor e tem sido associado a estados de dor persistente. Este estudo fisiológico duplo-cego e cruzado teve como objetivo investigar os efeitos da inibição do 5-HT3R com ondansetrona nos limiares térmicos e mecânicos de dor, avaliados por meio de teste sensitivo quantitativo (QST - quantitative sensory testing), e no CPM (estímulo térmico) em adultos saudáveis.

MÉTODOS: Dezessete voluntários saudáveis foram submetidos a avaliações de QST e CPM no início do estudo e após receberem uma infusão de 8 mg de ondansetrona ou solução salina (NaCl 0,9%) endovenosas. Uma semana depois, eles foram reavaliados usando o tratamento oposto seguindo o mesmo protocolo. As alterações no QST e na CPM antes e depois de cada intervenção foram analisadas por meio de testes t pareados ou testes de Wilcoxon(limiar de significância: p<0,05).

RESULTADOS: A ondansetrona não apresentou efeito significativo nas medidas do QST, mas aumentou significativamente o CPM em comparação com a solução salina.

CONCLUSÃO: Esses achados sugerem que a inibição do 5-HT3R aumenta a inibição endógena da dor sem alterar os limiares de dor aguda, destacando seu papel potencial na modulação central da dor.

Palavras-chave

Antagonistas do receptor de serotonina 5-HT3; Dor; Ondansetrona; Sensibilização do sistema nervoso central

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Submetido em:
03/11/2024

Aceito em:
17/05/2025