Continuous sumatriptan exposure induces persistent trigeminovascular sensitisation and brain perfusion changes in a rat model of medication overuse headache

Background

Repeated exposure to acute antimigraine medication can promote medication overuse headache, but the mechanisms underlying this transition remain incompletely understood. We used a clinically relevant rat model of continuous sumatriptan exposure to investigate whether medication overuse is associated with persistent sensitisation of the trigeminovascular system and longer-lasting changes in brain perfusion.

Methods

Adult male Sprague Dawley rats received continuous subcutaneous sumatriptan (0.6 mg/kg/day) or saline infusion for 6 days via osmotic minipumps. Periorbital and hindpaw mechanical thresholds were measured over 20 days. On day 6 and day 20, trigeminal ganglia and trigeminal nucleus caudalis were processed for immunohistochemistry for pERK, pp38, Iba-1, GFAP and NeuN. On day 20, a subgroup received sodium nitroprusside (SNP, 3 mg/kg, i.p.) to unmask latent sensitisation. Cerebral blood flow was assessed by MRI.

Results

Sumatriptan induced reversible cephalic and extracephalic allodynia. Previously exposed rats showed evidence of persistent sensitisation, including enhanced biomarker and glial responses after withdrawal and following SNP challenge. pERK and pp38 expression increased in both the trigeminal ganglion and trigeminal nucleus caudalis. In the TNC, marker association shifted over time from predominantly neuronal at day 6 to greater apparent glial association at day 20. Iba-1 and GFAP expression increased after withdrawal of sumatriptan and was further enhanced by SNP challenge. Within the TNC, neuronal marker expression was greatest in the ophthalmic representation. Sumatriptan exposure also produced a persistent reduction in cerebral blood flow that remained evident after behavioural recovery.

Conclusion

Continuous sumatriptan exposure produces prolonged trigeminovascular neuronal and glial alterations together with persistent changes in brain perfusion. These data support a state of latent sensitisation after repeated triptan exposure and provide mechanistic insight into medication overuse headache.

HIGHLIGHTS

• Repeated sumatriptan exposure induces reversible cephalic and extracephalic allodynia but leaves persistent trigeminovascular sensitisation after drug withdrawal.

• pERK and pp38 expression increase in the trigeminal ganglion and trigeminal nucleus caudalis, with the strongest regional changes seen in the ophthalmic representation of the TNC.

• Delayed increases in Iba-1 and GFAP in the TNC suggest that glial activation may contribute to maintenance of latent sensitisation, although the colocalisation findings are qualitative and should be interpreted cautiously.

• Repeated sumatriptan exposure is also associated with a persistent reduction in cerebral blood flow, indicating longer-lasting changes in brain perfusion beyond the period of overt allodynia.