PAIN RELIEVER EFFECT OF 2-SUBSTITUTED IMIDAZOLINE DERIVATIVES IN A RAT MODEL OF PERIPHERAL NEUROPATHY

Neuropathic pain affects millions of people worldwide causing substantial disability and greatly impairing quality of life. Commonly used analgesics or anti-hyperalgesic compounds are generally characterized by limited therapeutic outcomes. The 5‐hydroxytryptamine receptor subtype 5‐HT1A is involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since 5‐HT1A agonists may modulate the nervous signaling altered by neuropathies, the present research aimed to study novel 5‐HT1A ligands in a rat model of neuropathic pain induced by the chronic constriction injury (CCI) of the sciatic nerve. (S)-(-)-1 emerged as a potent and long-lasting antinociceptive agent in previous algesiometric paradigms.1 In addition, (S)-(-)-1 proved to be able to interact with 5-HT1A receptor. Fourteenth days after injury, the acute administration of low doses of (S)-(-)-1 (0.36-1.08 mg/kg, per os - p.o.) was able to significantly increased the pain threshold to noxious stimuli longer than 1 h. (S)-(-)-1 efficacy was confirmed reducing spontaneous pain. The clinically used compound gabapentin (100 mg/kg intraperitoneally – i.p.) induced a pain reliever effect slightly higher than (S)-(-)-1 administered at 100 fold lower dose (1.08 mg/kg). Furthermore, the selected compounds 2-6, analogues of (S)-(-)-1 and endowed with significant 5-HT1A receptor affinity, were tested (1 mg/kg p.o.) in the same model. All compounds were effective 30 min after administration. In particular 6 fully reverted the CCI-induced hypersensitivity. The co-administration of 6 with the selective 5-HT1A receptor antagonist WAY 100635 (1 mg/kg i.p. 15 min before 6) partially reverted the pain reliever effect of the new synthesized compound suggesting the relevance of the serotoninergic system modulation in its pharmacodynamic mechanism.