Selective targeting of peripheral cannabinoid receptors prevents behavioral symptoms and sensitization of trigeminal neurons in mouse models of migraine and medication overuse headache

Abstract

Migraine affects ∼15% of the world's population greatly diminishing their quality of life. Current preventative treatments are effective in only a subset of migraine patients, and although cannabinoids seem beneficial in alleviating migraine symptoms, central nervous system side effects limit their widespread use. We developed peripherally restricted cannabinoids (PRCBs) that relieve chronic pain symptoms of cancer and neuropathies, without appreciable central nervous system side effects or tolerance development. Here, we determined PRCB effectiveness in alleviating hypersensitivity symptoms in mouse models of migraine and medication overuse headache. Long-term glyceryl trinitrate (GTN, 10 mg/kg) administration led to increased sensitivity to mechanical stimuli and increased expression of phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment, but not posttreatment, prevented behavioral and biochemical correlates of GTN-induced sensitization. Low pH-activated and allyl isothiocyanate-activated currents in acutely isolated trigeminal neurons were reversibly attenuated by PRCB application. Long-term GTN treatment significantly enhanced these currents. Long-term sumatriptan treatment also led to the development of allodynia to mechanical and cold stimuli that 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 phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment prevented all behavioral and biochemical correlates of allodynia and latent sensitization. Importantly, long-term 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 medication overuse headache.

Involvement of TRPM2 in the Neurobiology of Experimental Migraine: Focus on Oxidative Stress and Apoptosis

“…Two members of the TRP superfamily are TRPA1 and TRPV1 channels, and they are also activated by OS [8,13]. The involvements of TRPA1 and TRPV1 on the GTNmediated migraine and pain models were recently reported [55][56][57]. Within the OS-dependent-activated TRP channels, TRPM2 is first discovered channel [15,16].…”

New Oral Drugs for Migraine

“…The complexities of these pathways and their interactions, particularly with the opioid pathway [140], make the ascertaining of a useful response to migraine difficult to clarify, despite the known analgesic effect of cannabinoids in chronic pain conditions [141]. There is some evidence that use of peripherally restricted cannabinoids, that is, those that do not enter the central nervous system, hence do not have central adverse effects, or contribute to medication overuse, may still be useful in treating allodynia as a surrogate of central sensitisation in a mouse model [142]. The increasing availability of overthe-counter synthetic cannabinoids is leading to increased numbers of patients using these agents for headache control or asking about them.…”

The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

“…JD5037 is a peripherally restricted CB 1 inverse agonist developed by Jenrin Discovery and licensed to Corbus Pharmaceuticals (now CRB-4001), which is due to begin phase 1 testing in the first half of 2022 (https://www.corbuspharma.com/our-pipeline/ endocannabinoid-system (accessed on 10 September 2021)). [85,105] Prader-Willi syndrome [88] Chronic kidney disease [101] Diabetic nephropathy [93] Alcoholic liver steatosis [94] Alcoholism [99,100] Non-alcoholic liver steatosis [96] Obesity-related liver steatosis [95] Liver fibrosis [102] Pulmonary fibrogenesis [97,98] Skin fibrosis [103] Inflammatory pain [106,107] Neuropathic pain [107,108] Bone cancer pain [109] Chemotherapy-induced pain [110] Migraine and medication overuse headache [111] Spasticity in multiple sclerosis [112] Gastrointestinal motility in colitis [42,43] Anticipatory nausea [113] Cardiac disease [114] Neuropathic pain [115] Chemotherapy-induced neuropathy [116] Inflammatory pain [115,117,118] Diabetic neuropathy [119] Visceral pain [115] Migraine [120,121] Anticipatory nausea [113] Cystitis [122] Bladder overactivity [123] Gastric lesions [118] Clinical research INV-101 in Prader-Willi syndrome (PWS) and non-alcoholic steatohepatitis (NCT04531150) (Inversago Pharma) TM38837 in healthy subjects [104] (7TM Pharma) GFB-024 in diabetic nephropathy (Goldfinch Bio, NCT04880291) AZ...…”

“…However, a lack of efficacy in clinical studies [124,125] meant the pharmaceutical development of these medicines was terminated. However, preclinical research with peripherally restricted CB 1 agonists continues in cancer-related pain [109,110] and migraine [111]. Other indications that have been investigated with a peripherally restricted CB 1 agonist included spasticity in multiple sclerosis [112], gastrointestinal motility issues [42,43], and anticipatory nausea [113], although none of these have been taken to clinic (see Table 2).…”