Final Report:  Stress-and Triptan-Induced Latent Sensitization: Neural Dynamics Underlying Migraine and Medication Overuse Headache

Summary

We recently developed synthetic peripherally-restricted cannabinoids (PRCBs) that don’t cross the blood-brain barrier and demonstrated their effectiveness in relieving chronic pain symptoms following traumatic peripheral nerve injury, cancer, and chemotherapy-induced neuropathy, without CNS side effects or development of tolerance. These compounds enabled us for the first time, to test the role of peripheral CB1 receptors (CB1Rs) in alleviating headache behaviors in preclinical models. Our preliminary studies showed a PRCB’s effectiveness in preventing the development of both acute and chronic hypersensitivity in mouse migraine models, as well as preventing the development of triptan- or stress-induced latent sensitization. We now propose a detailed examination of the specific mechanisms involved in the development of latent sensitization and its prevention by selective activation of peripheral cannabinoid receptors. Thus, our Specific Aims (SAs) are designed to utilize behavioral, pharmacological, biochemical, and electrophysiological techniques to probe the mechanisms of latent sensitization and the mechanisms by which selective activation of peripheral cannabinoid receptors protects against the development of neural sensitization and chronic migraine.

Hypothesis vs. Findings

We determined PRCB effectiveness in alleviating hypersensitivity symptoms in mouse models of migraine and medication overuse headache (MOH). Chronic glyceryl trinitrate (GTN, 10 mg/kg) administration led to increased sensitivity to mechanical stimuli, and increased expression of phosphorylated protein kinase A (p-PKA), neuronal nitric oxide synthase (nNOS), and transient receptor potential ankyrin 1 (TRPA1) proteins in trigeminal ganglia. PRCB pretreatment, but not posttreatment, prevented behavioral and biochemical correlates of GTN-induced sensitization. Low pH- and allyl isothiocyanate-activated currents in acutely isolated trigeminal neurons were reversibly attenuated by PRCB application. Chronic GTN treatment significantly enhanced these currents. Chronic sumatriptan treatment also led to development of allodynia to mechanical and cold stimuli which was slowly reversible after sumatriptan discontinuation. Subsequent challenge with a previously ineffective low-dose GTN (0.1-0.3 mg/kg) revealed latent behavioral sensitization and increased expression of p-PKA, nNOS, and TRPA1 proteins in trigeminal ganglia. PRCB pretreatment prevented all behavioral and biochemical correlates of allodynia and latent sensitization. Importantly, chronic PRCB treatment alone did not produce any behavioral or biochemical signs of sensitization. These data validate peripheral cannabinoid receptors as potential therapeutic targets in migraine and MOH.

Unanswered Questions

The GTN migraine model involves high-dose GTN injection which may cause various adverse systemic changes (e.g., cardiovascular effects) not related to hyperalgesia, as well as widespread nociceptive effects not related to migraine. Future studies will need to consider using migraine models which produce selective sensitization of dural afferents. We demonstrated increased function and expression of only a few ligand-gated ion channels and other biomarkers of trigeminal neuron sensitization. Future studies will need to address the involvement of other ligand- and voltage-gated ion channels (e.g., voltage-gated sodium channel 1.9, recently shown to contribute to GTN- and sumatriptan-induced behavioral sensitization) and other second messengers (e.g., PKCe, shown to be critical in hyperalgesic priming, a model of acute to chronic pain transition). Also, we only examined allodynia symptoms, but not the autonomic symptoms of migraine such as nausea, photophobia, and phonophobia. Further study will need to determine the efficacy of PRCBs such as PrNMI in alleviating the autonomic symptoms of migraine.

What This Research Means To You

We are excited that our synthetic peripherally-restricted cannabinoids have shown efficacy in preventing the development of acute and chronic hypersensitivity in models of migraine and medication overuse headache. Our goal now is to continue efforts at development of these novel compounds towards clinical trials. We are also continuing to study the cellular mechanisms of trigeminal sensitization particularly as it pertains to the interplay between the sensory innervation of the dura and the resident mast cells.