ArticleThe journal of headache and pain2026
Distribution and subacute modulation of endocannabinoid metabolizing enzymes in the trigeminal complex and midbrain in a pre-clinical model of post-traumatic headache.
Article in The journal of headache and pain, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPost-traumatic headache (PTH) is a debilitating neurological sequela of mild traumatic brain injury (mTBI) characterized by secondary cephalic pain. The endocannabinoid system (ECS) is a critical modulator of nociception, yet the specific spatiotemporal changes in its metabolic machinery within cephalic pain circuits following mTBI are poorly understood.
methodsUsing in-situ hybridization (ISH), we first characterized the levels of gene expression of major endocannabinoid (eCB) synthesizing enzymes (Napepld, Gde1, Dagla, Daglb), hydrolyzing enzymes (Faah, Mgll) and cannabinoid receptors (Cnr1 and Cnr2) in the trigeminal complex (trigeminal ganglion - TG, trigeminal root entry zone - TREZ, and trigeminal nucleus caudalis - TNC) and midbrain (periaqueductal gray - PAG, dorsal raphe - DR) regions involved in the modulation of pain. Subsequently, employing a mouse model of repetitive closed head mTBI that induces cephalic pain, we assessed global eCB enzymatic gene expression changes via qPCR and region-specific changes via ISH at one-week post-injury.
resultsBaseline characterization revealed complex co-expression patterns, with Gde1 and Daglb transcripts being significantly more abundant than Napepld and Dagla in the TG, TNC, and PAG. Seven days post-mTBI, coinciding with the onset of PTH-like symptoms, we identified a significant upregulation of the hydrolyzing enzymes Faah in the peripheral TREZ but not in the TG sensory neurons. Centrally, although no difference was observed in the TNC, mTBI induced an upregulation of Mgll in the ventrolateral PAG (vlPAG) and the DR, particularly within DR VGlut3+ neurons.
conclusionThese findings demonstrate a novel neuropathological mechanism whereby mTBI triggers a persistent, region-specific upregulation of genes encoding eCB-degrading enzymes. Thus, sub-acute modulation of eCB hydrolyzing enzymes in critical peripheral and central pain-modulating regions may contribute to the maintenance of cephalic pain associated with mTBI. CLINICAL TRIAL NUMBER: Not applicable.
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