Journal of Headache and Pain最新文献

Background: Migraine is the second leading cause of neurological disability and has a strong genetic component. Previous linkage studies have identified a candidate migraine susceptibility locus on chromosome Xq24-28, which harbors several GABA_A receptor subunit genes. Despite its inhibitory role in the central nervous system, the contribution of the GABAergic system to migraine pathophysiology remains insufficiently understood. This study elucidates the role of GABAergic neurons in chronic migraine using established rodent models. We induced basal hypersensitivity as a preclinical model of chronic migraine by administering repeated intraperitoneal injections of nitroglycerin, a well-established migraine trigger, every other day over a nine-day period. Mechanical hypersensitivity, a hallmark of migraine-associated allodynia, was assessed using von Frey filaments, before and after NTG treatment. NTG-treated animals exhibited a progressive increase in mechanical sensitivity compared to controls, consistent with the development of a chronic migraine-like state.

Results: Notably, a selective reduction in GABAergic neurons was observed in male, but not female, NTG-treated mice, specifically within key brain regions associated with pain processing and psychiatric circuits, from the locus coeruleus in the brainstem through the basal forebrain (notably the amygdala) to the neocortex and hippocampus. This loss of GABAergic neurons was accompanied by elevated expression of ΔFosB, a marker of sustained neuronal activation, and increased apoptotic signaling indicated by active caspase-3 staining. Furthermore, male chronic migraine mice showed upregulation of stress-related neuropeptides, including PACAP and its receptor PAC1, as well as downstream effectors BDNF and TRK1B. Gene expression analysis revealed downregulation of GABA signaling components in the choroid plexus of the fourth ventricle, including aberrant overexpression of the chloride cotransporter NKCC1.

Conclusion: These findings reveal a male-specific vulnerability of GABAergic neurons in chronic migraine and suggest a sex-dependent divergence in the underlying pathophysiological mechanisms. This highlights the critical need for sex-specific approaches to migraine research and therapeutic development.

Background: Emerging biopsychosocial perspectives emphasize the complex interplay between psychological burden and migraine, particularly during young adulthood-a period marked by neurodevelopmental vulnerability and shifting social roles. However, gender-specific associations and the modifying role of marital status in this context remain poorly understood.

Methods: This population-based study analyzed 3,180 U.S. young adults aged 20-39 years using the 1999-2004 National Health and Nutrition Examination Survey. Migraine was identified via self-reported symptoms and medication use; psychological disorders were assessed using standardized CIDI modules consistent with DSM-IV. Gender-stratified multivariable logistic regression models were used to examine the associations between migraine and three psychological disorders: depressive disorder, generalized anxiety disorder, and panic disorder. Interaction terms were incorporated to assess effect modification by marital status.

Results: Among young adult male participants, both depressive disorder (OR = 2.59, 95% CI: 1.01-6.67) and panic disorder (OR = 2.28, 95% CI: 1.03-5.07) were significantly associated with migraine. Marital status modified the panic-migraine association, with the strongest risk observed in those widowed/divorced/separated. In contrast, among young adult female participants, only generalized anxiety disorder demonstrated a robust association with migraine (OR = 2.87, 95% CI: 1.59-5.16), and a similar marital gradient was observed.

Conclusions: This study highlights distinct gender-based psychological correlates of migraine and reveals the social context of marital status as a potential modifier. These findings underscore the need for sex-sensitive and psychosocially informed strategies in migraine assessment and intervention, aligning with biopsychosocial models of pain and the goals of integrated headache care.

Background: Current etiology-centered management guidelines have not brought about satisfactory outcomes for trigeminal neuralgia patients. Therefore, there is an urgent call for pathology-targeted diagnosis and treatment modalities for this intractable disease. Trigeminal root demyelination has been frequently shown or suggested in trigeminal neuralgia patients of diverse etiologies and then naturally regarded as the common pathological cause of this disease. However, this causal relationship has never been validated so far with success in either preclinical or clinical studies. One of the key obstacles is that trigeminal root demyelination per se has not been proven as yet to be sufficient to induce trigeminal neuralgia-like facial pain in animals.

Methods: Trigeminal root demyelination was directly induced by MRI-informed stereotactic microinjection of (1) myelin-destructive lysophosphatidylcholine into both extrapontine and intrapontine trigeminal roots of adult rats and (2) recombinant adeno-associated virus that genetically ablates myelin-forming oligodendrocytes via apoptosis into trigeminal root entry zones of adult mice. Long-lasting asymmetric eyelid contraction and asymmetric cluster face-stroking were adopted as the affective and motivational behavioral proxies to assess facial pain. More importantly, carbamazepine versus pregabalin treatment and chemical silencing of primary nociceptive afferents were used to ascertain the resemblance of facial pain in rodent models to trigeminal neuralgia in patients.

Results: Chemically or viral genetically induced demyelination in trigeminal root entry zones were shown to induce facial pain behaviors in adult rats and mice. More importantly, facial pain in these rodent models was shown to resemble patient trigeminal neuralgia in terms of the preferred responsiveness to carbamazepine and the unique requirement of primary nociceptive afferents. Moreover, focal demyelination in adult rat intrapontine trigeminal roots was also shown to induce trigeminal neuralgia-like facial pain.

Conclusions: Trigeminal root demyelination is sufficient to induce trigeminal neuralgia-like facial pain in adult rodents. Our noteworthy findings would support trigeminal root demyelination as the common pathological cause of trigeminal neuralgia. This advancement will promote pathological conceptualization and clinical management of this etiologically heterogeneous disease as a unified entity of demyelinating disorders. Meanwhile, a group of simple and reliable pathological rodent models were provided for further investigations into trigeminal neuralgia.

Background: Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology and is a marker of trigeminal activity. We investigated tear fluid CGRP levels interictally and ictally using the glyceryl trinitrate (GTN) experimental migraine model.

Methods: Study participants were assessed interictally and during an experimental headache using GTN. Interictal tear fluid CGRP levels were assessed in episodic migraine (EM) patients and healthy controls (HC). At the day of experimental headache, tear fluid was sampled in EM patients before and after intravenous GTN application. Participants were free to use their usual abortive medication if needed. Tear fluid CGRP levels were analyzed using two different ELISAs.

Results: 26 EM patients and 20 healthy controls were examined interictally. Interictal tear fluid CGRP was significantly higher in EM patients compared to HCs (Abbexa® CGRP ELISA: interictal EM patients: 2.78 ± 1.99 ng/ml, HC: 1.35 ± 0.78 ng/ml, U = -2.969, p = 0.003). 17 EM patients were analyzed after intravenous GTN. Tear fluid CGRP levels were significantly elevated at maximum headache compared to baseline (Abbexa® CGRP ELISA: 3.84 ± 1.96 ng/ml vs. 2.78 ± 2.38 ng/ml, p = 0.025; Cusabio® CGRP ELISA: 1.43 ± 0.96 ng/ml vs. 0.75 ± 0.77 ng/ml, p < 0.001). Seven patients developed a headache with an intensity ≥ 5 on the numerical rating scale (NRS) and showed a significantly higher rise in tear fluid CGRP compared to patients with a headache < 5 on the NRS (Abbexa® CGRP ELISA: + 2.11 ± 2.14 ng/ml vs. + 0.32 ± 1.33 ng/ml, p = 0.033; Cusabio® CGRP ELISA: + 1.45 ± 0.81 ng/ml vs. + 0.09 ± 0.53 ng/ml; p < 0.001). Tear fluid CGRP levels were significantly more reduced after intake of abortive medication than after spontaneous headache improvement (Abbexa® CGRP ELISA: -0.82 ± 1.26 ng/ml vs. 1.24 ± 2.06 ng/ml, p = 0.014; Cusabio® CGRP ELISA: -0.66 ± 1.27 ng/ml vs. -0.12 ± 0.24 ng/ml, p = 0.033).

Conclusion: The present results demonstrate validity of tear fluid CGRP assessment during experimental migraine, detecting a rise of tear fluid CGRP levels during GTN-induced headache. The intake of abortive medication reduced tear fluid CGRP levels significantly more than spontaneous headache improvement.

Background: There is evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of CSD initiation in the brain of migraineurs remain unknown. Insights into this question can be obtained by studying the mechanisms underlying the facilitation of CSD initiation in genetic mouse models of migraine. Here, we investigated these mechanisms in knock-in mice carrying a mutation in the Ca_V2.1 calcium channel, which causes pure familial hemiplegic migraine type 1 (FHM1 mice).

Methods: Brief high-KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded in cortical slices from FHM1 mice. This was done before and after application of MK-801. After blocking the glutamate NMDA receptors (NMDARs), stimuli up to 21 times the control CSD threshold were applied.

Results: A delayed activation of NMDARs above a critical threshold level is necessary for CSD initiation in FHM1 mice. This threshold level of NMDAR activation is quantitatively similar in FHM1 and WT mice, but is reached with a stimulus of much lower intensity and more rapidly in FHM1 mice, thus accounting for the facilitation of CSD initiation in these migraine mouse models. While, no matter the intensity of stimulation, Ca_V channels are necessary for CSD initiation, the necessity of NMDARs can be overcome by largely suprathreshold stimuli in FHM1 mice; however, these NMDAR-independent CSDs propagate much more slowly than the control CSDs, due to both a longer time needed to reach the threshold for CSD initiation after the beginning of the prodromal neuronal depolarization and a slower regenerative CSD depolarization.

Conclusions: FHM1 mice are more susceptible to CSD initiation than WT mice because the critical threshold level of NMDAR activation, necessary for CSD initiation in both genotypes, is attained with stimuli of much lower intensity and more rapidly in FHM1 mice. Our findings give insights into potential mechanisms of CSD initiation in migraine.