The role of nitrergic system on the effects of tramadol and agmatine in an experimental neuropathic pain model

Neuropathic pain (NP) which reduces significantly quality of life usually resistant to common analgesics. Some second-indication drugs such as tricyclic antidepressants, anticonvulsants and local anesthetics have been used in the treatment of NP, howewer they are usually not fully effective. In the last years some studies have been reported that tramadol reduced the symptoms of neuropathic pain. On the other hand, recent studies suggests that agmatine might be an important neurotransmitter in central nervous system and has potential as a treatment of pain. The present study determined the antiallodynic effects of tramadol and agmatine alone and with combination and the involvement of nitric oxide in these effects. Male balb/c mice were used in all experiments. Experimental mononeuropathy was developed by ligation of right sciatic nerve of mice under general anesthesia. Mice were divided into naive, sham, neuropathy control (NP), and NP + drugs groups. Neuropathic pain was tested by cold allodynia using cold-plate test on day 14 after operation. The antiallodynic effects of tramadol and agmatine were assessed. Nitric oxide precursor L-arjinin (LA), nitric oxide synthase (NOS) inhibitors L-NAME, L-NMMA and 7-NI were used to investigate the role of nitric oxide in these effects,. Lastly, the combined effects of tramadol and agmatine was determined. Cold plate latency (CPL) was decreased significantly in NP groups compared to naive and sham-operated groups. These results show that neuropathy was developed in sciatic nerve ligated mice. Tramadol and agmatine showed antiallodynic effect by enhance CPL. LA did not changed the effects of tramadol and agmatine. All NOS inhibitors enhanced the antiallodynic effect of tramadol while only L-NAME enhanced the effect of agmatine. The combined use of tramadol and agmatine showed greater antiallodynic effect than the effects of individual drugs. According to findings, tramadol and agmatine are promising drugs for treatment of NP and combined use of these drugs may be more effective. The role of inhibition of NOS in the antiallodynic effects of these two drugs were different in extent. Other possible mechanisms beside NOS inhibition may involve in the effects of these two drugs.