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Synthetic non-psychoactive cannabinoid prevents hypersensitivity symptoms in mouse migraine models


Migraine headache affects ~15% of the world’s population, greatly diminishing sufferers’ quality of life. Injection of glyceryl trinitrate (GTN), a known migraine trigger in humans, produces hypersensitivity symptoms of allodynia and hyperalgesia in a previously developed mouse model of migraine headache. We developed synthetic non-psychoactive peripherally-restricted cannabinoids (PRCBs) and demonstrated their effectiveness in relieving cancer and neuropathic pain symptoms. Here, we investigated the efficacy of one of our novel PRCBs, PrNMI, in preventing the symptoms of GTN-induced hypersensitivity in C57BL/6J female mice. Von Frey filaments were used to assess GTN (10 mg/kg, i.p.)-induced changes in head or hindpaw withdrawal thresholds. Selective cannabinoid 1 receptor (CB1R) and CB2R antagonists were used to examine receptor subtype contribution to PrNMI’s effects. Following behavioral assessments, collected trigeminal ganglia (TG) were analyzed for various protein biomarkers of TG neuron sensitization utilizing an automated capillary electrophoresis system. Separately, whole-cell patch clamp recordings from acutely isolated TG neurons assessed changes in the activation of low pH- and allyl isothiocyanate-induced currents. Results showed that PrNMI (0.6 mg/kg, i.p.) prevented the development of both acute and chronic hypersensitivity induced by GTN injections. Both CB1R and CB2R activation contributed to PrNMI’s suppression of acute GTN-induced hypersensitivity. Repeated GTN administration significantly increased ion channel, enzymes and second messenger markers of trigeminal sensitization, which were prevented by PrNMI pretreatment. Chronic GTN treatment (10 mg/kg) increased activation of low pH- and allyl isothiocyanate-induced currents in TG neurons, while PrNMI reversibly (1 M) suppressed both of these currents in TG neurons of na�ve mice. These results demonstrate the efficacy of PrNMI as a putative preventative therapeutic for chronic migraine.

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