Background: Monoaminergic pathways, impinging an adrenergic and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions has not been clarified yet.
Objectives: The study was designed to investigate the influence of the neonatal noradrenergic system lesion on the antinociceptive effect of 5-HT3 receptor ligands assessed in adult animals.
Material and methods: Intact male rats were contrasted with rats in which noradrenergic nerve terminals were largely destroyed shortly after birth with neurotoxin DSP-4 [(N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine; 50 mg/kg × 2 subcutaneously (sc)], on the 1st and 3rd days of postnatal life. Control animals were injected with saline (1.0 mL/kg sc). When the rats attained 10 weeks of age, painful reactions were assessed by means of writhing and formalin tests after intraperitoneal (ip) administration of 1-phenylbiguanid (FBG; 7.5 mg/kg) or ondansetrone (1.0 mg/kg) with FBG (7.5 mg/kg). Morphine was used as a model analgesic drug.
Results: Injections of morphine (7.5 mg/kg sc) evoked similar antinociception in the visceral pain model (writhing test) in both tested groups (control and DSP-4). In control rats, a 5-HT₃ receptor agonist FBG (7.5 mg/kg) elicited analgesia similar to that of morphine but the effect was significantly lower in DSP-4 treated animals. A 5-HT₃ receptor antagonist ondansetrone (1.0 mg/kg) injected before FBG did not modify the effect in the control but suppressed it in the DSP-4 group. In the formalin test, morphine produced higher analgesia in control rats in comparison with the DSP-4 group (pain intensity score of 1 point vs. 2-3 points, respectively). Ondansetrone injected before FBG alleviated the observed effect.
Conclusions: Based on the obtained results, we concluded that the neonatal DSP-4 treatment alters the antinociceptive effects of morphine and serotoninergic 5-HT₃ receptor ligands. The above may explain altered (diminished) reactions of analgesics applied to patients with noradrenergic system dysfunction (e.g. depression and/or anxiety disorders).