Effects of Chronic Anandamide Administration and The Role of Nitric Oxide on Cisplatin Induced Peripheral Neuropathy in Rats

Abstract

Background: Cisplatin (CIS) is an effective antineoplastic agent used in treatment of several cancer types. However, peripheral neuropathy is a major side-effect seen in most of patients. Cannabinoids are known to have a potential analgesic effect. The aim was to investigate the antinociceptive effects of chronic administration of anandamide (AN), a cannabinoid receptor agonist, on cisplatin-induced neuropathy and involvement of nitric-oxide (NO) in this effect.

Methods: Female Sprague Dawley rats were divided into four groups:control, CIS, CIS+AN, CIS+AN+LNAME. CIS was administered 3mg/kg/ip once weekly for five weeks. Saline(2ml) was also given to prevent nephrotoxicity. AN (1mg/kg/ip) or in combination with 10mg/kg/ip L-NAME was administrated 30 min before every cisplatin injection. Mechanical allodynia, thermal hyperalgesia using analgesia-meter and tail clip tests were performed on the 6th day of each drug injections and hind paw, tail withdrawal latencies were recorded. At the end of the drug administration, rats were fixed by intracardiac perfusion. Right sciatic-nerves (SN) and associated dorsal root ganglion (DRG) were isolated and were stained with toluidine blue. Sections were observed under light microscope. Data were analyzed with SPSS 21.0 and p<0.05 was accepted as significant.

Results: CIS decreased hind paw withdrawal latency in mechanical allodynia test, but didn't alter this latency in thermal hyperalgesia test. AN didn't change hind paw withdrawal latency in mechanical allodynia test, whereas increased it in thermal hyperalgesia. In L-NAME group, there were no significant differences in the effects of AN. No significant change was detected in tail clip test in groups. In assessment of SN, the ratio of degenerate/normal axons significantly increased in CIS group, AN decreased while L-NAME increased this effect. In AN group, soma area of DRG neurons in the range of 801-1000microm2 significantly were higher than those of CIS+AN.

Conclusions: Our results indicate that chronic AN treatment attenuated CIS-induced neuropathy in thermal hyperalgesia test and decreased ratio of degenerate/normal axons. In AN group there was increase in big size neurons as compared to CIS group. However, NO seems not to be involved in this effect.

This study is supported by Eskisehir Osmangazi University Commission of Scientific Researches under the Project Number:2016-984.