Nitroglycerin challenge induces lateralized headache in nasociliarynerve-ligated rats: implications for chronic migraine.

OBJECTIVE

Chronic migraine is a common debilitating disease with limited treatment options. We aimed to develop a novel model for chronic migraine by ligating the nasociliary nerve (NCL) and administering nitroglycerin (NTG) to exacerbate acute headache attacks.

METHODS

Exacerbation of the headache was induced by NTG (10 mg/kg, subcutaneously) administered to male Wistar rats (n = 36) 14 days following unilateral NCL. Cutaneous and cold allodynia was tested using Von Frey (VF) filaments and acetone, respectively. Elevated plus maze (EPM) results and c-fos immunoreactivity of TNC were investigated.

RESULTS

NTG administration significantly decreased VF threshold values only in the nasociliary nerve (NCN) territory and the ipsilateral forepaw (P = 0.0001, P = 0.02). Cold allodynia developed in bilateral NCN territories (P = 0.013). The number/rate of entrance to open arms in the EPM was significantly decreased in NCN-ligated rats (P = 0.042, P = 0.035). Immunohistochemistry disclosed significantly increased c-fos-positive neurons in ipsilateral brainstem TNC compared to the contralateral side (brain stem LI ipsilateral 25.4 ± 4.7, contralateral 11.8 ± 1.9, P < 0.05) in chronic NCN-ligated rats exposed to acute NTG.

CONCLUSIONS

The presented model provides a valid chronic migraine model relevant to humans, as NTG challenge in chronic NCL rats generated lateralized headache with cephalic and extracephalic allodynia, altered cold sensitivity, anxiety, and neuronal activation in the nociceptive laminae of brainstem trigeminal pain nuclei.