Influence of central noradrenergic system lesion on the serotoninergic 5-HT3 receptor mediated analgesia in rats

Monoaminergic pathways, impinging an adrenergic and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions has not been clarified yet.

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.

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.

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.

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).