Venlafaxine as Monotherapy and in Combination Regimens in Acute Rodent Nociception Experimental Models: A Review.

Abstract

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose-response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed.