Effect of single and repeated administration of amitriptyline on neuropathic pain model in rats: Focus on glutamatergic and upstream nitrergic systems

Few studies have compared the interaction of single and repeated administration of amitriptyline (amit) with the nitrergic system and glutamatergic system in the experimental model of neuropathic pain. We aimed to evaluate the antinociceptive effect of single and repeated administration of amit and to assess whether glutamate preceded inducible nitric oxide synthase (iNOS) inhibition as a mechanism of the analgesic effect of amit in the neuropathic model of pain. Male Wistar rats were subjected to left sciatic nerve ligation. The effect of single (25 mg kg − 1 ) and repeated (10 mg kg − 1 daily for 3 weeks) administration of amit intraperitoneally (i.p.) alone or in combination with aminoguanidine (AG i.p., 100 mg kg − 1 for 3 days, a selective iNOS inhibitor) and MK-801 (0.05 mg kg − 1  i.p., NMDA antagonist) on resting paw posture and mechanical hyperalgesia were studied. Glutamate level and iNOS protein expression in hippocampus were detected. Single and repeated administration of amit alone or in combination with AG or MK-801 demonstrated a significant decrease in resting pain score and increase in the pain threshold. Both glutamate and nitrite levels decreased in the hippocampi of single and repeated amit + MK-801 groups. Immunohistochemistry showed a marked decrease in iNOS immunoreactivity in rats treated with single and repeated amit + MK-801. Our results suggest that glutamate-dependent mechanisms are involved in the analgesic responses to amit administration. Importantly, glutamatergic system and its upstream nitrergic system play an important role in the antinociceptive action of amit.