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This commentary discusses a recent publication by evolutionary biologists with strong implications for migraine experts. The Authors showed that a gene polymorphism associated with migraine gave our ancestors an evolutionary advantage when colonizing northern, and thus colder, territories. They then highlight that the prevalence of migraine may differ among countries because of climatic adaptation. These results may prove useful in planning both epidemiological and physiological studies in the field of migraine.
Learn More >Biomarkers indicating characteristic alterations in the brains of pain patients would in comparison to behavioral examinations allow for earlier diagnoses of pain disease development, a more immediate monitoring of pain disease progression, and for the development of interventions to reverse or compensate for the alterations. To reveal causal relations between an observed alteration and the pain disease longitudinal examinations are essential. Resting-state fMRI examinations can readily be included in large longitudinal cohorts allowing to achieve sufficiently large patient samples even for rare diseases. Our literature review on longitudinal resting-state fMRI examinations of pain patients indicates that pain chronicity is predicted by alterations to the brain's reward system and default mode network. A brain wide reorganization of the resting-state networks is associated with the emergence of the chronic pain state. The functional connectivity of the left frontoparietal network predicts the evolution of pain intensity in the chronic state. Further investigations are necessary concerning the generalization of the biomarkers across the phases in pain development especially for the healthy state, across different pain etiologies, and their specificity to chronic pain. The currently acquired representative longitudinal cohorts will allow for clarification of those issues within the next decades.
Learn More >Trigeminal neuralgia (TN) is the most common neuropathic pain in the facial area, for which the effective therapy is unavailable. Long non-coding RNA (lncRNA) such as lncRNA uc.48+ is involved in diabetic neuropathic pain and may affect purinergic signaling in ganglia of diabetic rats. In this research, chronic constriction injury of the infraorbital nerve (CCI-ION) was applied to establish a rat model of TN. Five days after local injection of siRNA targeting the lncRNA uc.48+ in trigeminal ganglia (TGs), the upregulated uc.48+ expression and the reduced mechanical withdrawal threshold (MWT) in the TN rats were significantly reversed. The expression of P2X receptor in TGs was increased in the TN group compared with the sham group, but uc.48+ siRNA treatment mitigated this effect. The phosphorylation of ERK1/2 in TGs of TN rats was significantly enhanced compared with the sham group, while uc.48+ siRNA treatment reversed this change. In addition, injection of the lncRNA uc.48+ overexpression plasmid in TGs of control rats significantly reduced the MWT but elevated the expression of P2X in TGs; the phosphorylation of ERK1/2 in TGs in these uc.48+-overexpressed rats was significantly higher, similar to the observations in rats of TN model. The interaction between uc.48+ and the P2X receptor was detected by RNA binding protein immunoprecipitation (RIP), indicating that P2X receptor could specifically bind to uc.48 + . In summary, knockdown of lncRNA uc.48+ by siRNA could inhibit transduction of TN signals, whereas uc.48+ overexpression promoted TN signal transduction. LncRNA uc.48+ may interact with P2X receptor to upregulate expression of P2X receptor and furthermore enhance the phosphorylation of ERK1/2 in TGs, thereby participating in pain transmission in TN.
Learn More >A study published in PAIN in 2010 showed remarkable effects of intradiscal methylene blue (MB) injections compared with placebo on pain intensity in patients with chronic discogenic low back pain (CD-LBP). Both groups received lidocaine hydrochloride injections for pain associated with the procedure. We replicated the design of the previously published study and performed a multicenter, double-blind, randomized, placebo-controlled trial to assess whether the extraordinary effects of MB on pain intensity could be confirmed. The primary outcomes were treatment success defined as at least 30% reduction in pain intensity and the Patients' Global Impression of Change 6 months after the intervention. We included 84 patients with CD-LBP of which 14 (35%) in the MB plus lidocaine group showed treatment success compared with 11 (26.8%) in the control group who received placebo plus lidocaine (P = 0.426). Twenty-seven percent of all participants treated with MB stated that their overall health improved much or very much (Patients' Global Impression of Change), vs 25.6% in the placebo group (P = 0.958). We were unable to confirm that intradiscal MB injections are better capable of significantly reducing pain in patients with CD-LBP 6 months after treatment compared with placebo. We observed that over one-quarter of patients receiving only lidocaine injections reported treatment success, which is in contrast with the previously published study. Our results do not support the recommendation of using intradiscal MB injections for patients with CD-LBP.
Learn More >Chronic alcohol use and withdrawal leads to increased pain perception, anxiety, and depression. These aberrant behaviors are accompanied by increased excitatory glutamatergic transmission to, and activity of, the lateral habenula neurons.Vanilloid type 1, or TRPV1, channels are expressed in the habenula and they facilitate glutamatergic transmission. Whether TRPV1 channel plays a role in habenula hyperactivity is not clear.
Learn More >Diabetic distal symmetrical peripheral polyneuropathy (DSP) results in decreased somatosensory cortical gray matter volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has examined whether changes in brain volume alters the functional organisation of the somatosensory cortex and how this relates to the different painful DSP clinical phenotypes. In this case-controlled, multimodal magnetic resonance brain imaging study of 44 carefully phenotyped subjects, we found significant anatomical and functional changes in the somatosensory cortex. Painful DSP insensate subjects have the lowest somatosensory cortical thickness with expansion of the area representing pain in the lower limb to include face and lip regions. Furthermore, there was a significant relationship between anatomical and functional changes within the somatosensory cortex and severity of the peripheral neuropathy. These data suggest a dynamic plasticity of the brain in DSP, driven by the neuropathic process. It demonstrates, for the first time, a pathophysiological relationship between a clinical painful DSP phenotype and alterations in the somatosensory cortex.
Learn More >Migraine is a complex neurological disorder characterized by severe headaches associated with a plethora of sensory hypersensitivity and neurovegetative symptoms. In about one-third of the cases, a set of fully reversible focal neurological symptoms, the aura, accompanies the headache. In the last decades, advanced neuroimaging investigations allowed identification of structural, microstructural, and functional abnormalities characterizing the brain of patients with migraine with aura (MwA). However, mechanisms underlying the aura phenomena are still a matter of debate.
Learn More >The commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent.
Learn More >Opioid misuse is a significant public health problem. Chronic pain is one highly prevalent factor that is strongly associated with increased risk for opioid misuse. Anxiety sensitivity (fear of anxiety related physical sensations) is an individual difference factor consistently linked to pain experience, and separately, heroin use. The present study examined if anxiety sensitivity may be one factor related to the relationship between pain intensity and opioid misuse among opioid-using adults with chronic pain. Results indicated that anxiety sensitivity total score was significantly associated with the relationship between pain intensity and current opioid misuse, as well as pain intensity and severity of opioid dependence. Overall, results suggest that anxiety sensitivity may be an important assessment and intervention target to ultimately reduce the rates of opioid misuse among adults with chronic pain.
Learn More >Glycine receptors (GlyRs) are pentameric proteins that consist of α (α1-α4) subunits and/or β subunit. In the spinal cord of adult animals, the majority of inhibitory glycinergic neurotransmission is mediated by α1 subunit-containing GlyRs. The reduced glycinergic inhibition (disinhibition) is proposed to increase the excitabilities and spontaneous activities of spinal nociceptive neurons during pathological pain. However, the molecular mechanisms by which peripheral lesions impair GlyRs-α1-mediated synaptic inhibition remain largely unknown. Here we found that activity-dependent ubiquitination of GlyRs-α1 subunit might contribute to glycinergic disinhibition after peripheral inflammation. Our data showed that HUWE1 (HECT, UBA, WWE domain containing 1), an E3 ubiquitin ligase, located at spinal synapses and specifically interacted with GlyRs-α1 subunit. By ubiquitinating GlyRs-α1, HUWE1 reduced the surface expression of GlyRs-α1 through endocytic pathway. In the dorsal horn of Complete Freund's Adjuvant-injected mice, shRNA-mediated knockdown of HUWE1 blunted GlyRs-α1 ubiquitination, potentiated glycinergic synaptic transmission and attenuated inflammatory pain. These data implicated that ubiquitin modification of GlyRs-α1 represented an important way for peripheral inflammation to reduce spinal glycinergic inhibition and that interference with HUWE1 activity generated analgesic action by resuming GlyRs-α1-mediated synaptic transmission.
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