Dipyrone induces sex-dependent latent sensitization in a preclinical model of medication overuse headache

The excessive use of medications for the symptomatic treatment of primary headaches can lead to the development of Medication Overuse Headache (MOH), a secondary chronic headache. It is considered that the excessive use of any over-the counter analgesic can induce MOH, but there is little preclinical and clinical evidence. This study aimed to evaluate whether prolonged exposure to dipyrone (metamizole) in both male and female rats induces MOH. First, the acute effect of dipyrone (60 mg/kg) was assessed in migraine-related responses induced by injection of calcitonin-gene related peptide (CGRP, 0.1 nmol/10 μL) in the trigeminal ganglion. Next, the animals were orally treated with dipyrone (120 mg/kg, 2 x day/30 days) and the periorbital mechanical threshold was assessed at 5-day intervals. At the end of the treatment, the animals were exposed to a bright light for allodynia reinstatement. Mechanical thresholds in the hindpaw region, locomotor activity as well as plasma levels of CGRP were also assessed. A single administration of dipyrone reduced periorbital mechanical allodynia induced by CGRP in male and female rats. Male and female rats treated with dipyrone for 30 days did not show any change in the periorbital mechanical threshold. However, chronic dipyrone induced latent sensitization, revealed by bright light exposure, selectively in females. Prolonged dipyrone treatment did not affect the paw mechanical threshold, the locomotory behavior, or the plasmatic levels of CGRP. These results suggest that prolonged treatment with dipyrone can cause sensitization of the trigeminal system and potentially induced MOH, with females being more vulnerable.