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Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N/N = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r = 0.11, P = 3.56 × 10) and systolic BP (SBP, r = 0.06, P = 0.01), but not pulse pressure (PP, r = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.
Learn More >Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.
Learn More >Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models.
Learn More >Cancer-induced bone pain (CIBP) can be challenging to manage in advanced cancer. The unique properties of methadone may have a role in refractory CIBP. We aimed to evaluate the analgesic effects of methadone for CIBP when other opioids are ineffective or intolerable.
Learn More >Primary objectives: to investigate the central neurobiological effects (using MRI) of physical exercise in individuals with chronic pain. Secondary objectives: (1) to investigate the associations between central changes and clinical outcomes and (2) to investigate whether different types and dosages of physical exercise exert different central changes.
Learn More >Neuropathic pain (NP) is directly caused by an injury or disease of the somatosensory nervous system. It is a serious type of chronic pain that is a burden to the economy and public health. Although recent studies have improved our understanding of NP, its pathogenesis has not been fully elucidated. Noncoding RNAs, including lncRNAs, circRNAs, and miRNAs, are involved in the pathological development of NP through many mechanisms. In addition, extensive evidence suggests that novel regulatory mechanisms among lncRNAs/circRNAs, miRNAs, and mRNAs play a crucial role in the pathophysiological process of NP. In this review, we comprehensively summarize the regulatory relationship among lncRNAs/circRNAs, miRNAs, and mRNAs and emphasize the important role of the lncRNA/circRNA-miRNA-mRNA axis in NP.
Learn More >Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated L-glutamate-evoked firing, but not in the presence of GABA antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABA antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.
Learn More >The micro (mi)RNAs expressed in the sciatic nerve of streptozotocin (STZ)-induced diabetic rats were evaluated in terms of their therapeutic potential in patients with diabetic neuropathic pain (DNP). Relative miRNA expression in sciatic nerve with DNP was analyzed using next-generation sequencing and quantitative PCR. Potential downstream targets of miRNAs were predicted using Ingenuity Pathway Analysis and the TargetScan database. In vitro experiments were performed using miR-133a-3p-transfected RSC96 Schwann cells. We performed micro-Western and Western blotting and immunofluorescence analyses to verify the role of miR-133a-3p. In vivo, the association between miR-133a-3p with DNP was analyzed via AAV-miR-133a-3p intraneural (intra-epineural but extrafascicular) injection into the sciatic nerve of normal rats or injection of an miR-133a-3p antagomir into the sciatic nerve of diabetes mellitus (DM) rats. miR-133a-3p mimics transfected into RSC96 Schwann cells increased VEGFR-2, p38α MAPK, TRAF-6, and PIAS3 expression and reduced NFκB p50 and MKP3 expression. In normal rats, AAV-miR-133a-3p delivery via intraneural injection into the sciatic nerve induced mechanical allodynia and p-p38 MAPK activation. In DM rats, miR-133a-3p antagomir administration alleviated DNP and downregulated p-p38 phosphorylation. Overexpression of miR-133a-3p in the sciatic nerve induced such pain. We suggest that miR-133a-3p is a potential therapeutic target for DNP.
Learn More >Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.
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