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Background <p>Post-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.</p> Methods <p>Using in-situ hybridization (ISH), we first characterized the levels of gene expression of major endocannabinoid (eCB) synthesizing enzymes (<i>Napepld</i>, <i>Gde1</i>, <i>Dagla</i>, <i>Daglb</i>), hydrolyzing enzymes (<i>Faah</i>, <i>Mgll</i>) and cannabinoid receptors (<i>Cnr1</i> and <i>Cnr2</i>) 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.</p> Results <p>Baseline characterization revealed complex co-expression patterns, with <i>Gde1</i> and <i>Daglb</i> transcripts being significantly more abundant than <i>Napepld</i> and <i>Dagla</i> 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 <i>Faah</i> 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 <i>Mgll</i> in the ventrolateral PAG (vlPAG) and the DR, particularly within DR <i>VGlut3</i>+ neurons.</p> Conclusion <p>These 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.</p> Clinical trial number <p>Not applicable.</p>

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Distribution and subacute modulation of endocannabinoid metabolizing enzymes in the trigeminal complex and midbrain in a pre-clinical model of post-traumatic headache

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  • 发表日期：

    2026年4月11日

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  • Gurueswar Nagarajan,
  • Yumin Zhang

摘要

Background

Post-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.

Methods

Using 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.

Results

Baseline 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.

Conclusion

These 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.