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Transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1, respectively) channels contribute to inflammatory and neuropathic pain, indicating that their pharmacological inhibition could be a novel strategy for treating painful diseases. However, the mechanisms of TRPA1/V1 channel modulation have been mostly characterized to be upregulation and sensitization via variety of exogenous stimuli, endogenous inflammatory mediators, and metabolites of oxidative stress. Here we used calcium imaging of dorsal root ganglion neurons to identify an inhibitor signaling pathway for TRPA1 and TRPV1 regulated by resolvins (RvD1 and RvE1), which are endogenous anti-inflammatory lipid mediators. TRPA1 and TRPV1 channel activations were evoked by the TRPA1 agonist allyl isothiocyanate and the TRPV1 agonist capsaicin. Our results show that RvD1-induced selective inhibition of TRPA1 activity was mediated by free fatty acid receptor 4 (FFAR4)-protein kinase C (PKC) signaling. Experiments assessing RvE1-induced TRPV1 inhibition showed that RvE1 actions required both FFAR1 and FFAR4. Combined stimulation of FFAR1/FFAR4 or FFAR1/PKC mimicked TRPV1 inhibition by RvE1, and these effects were blocked by a protein kinase D (PKD) inhibitor, implying that PKD is an effector of the FFAR/PKC signaling axis in RvE1-induced TRPV1 inhibition. Despite selective inhibition of TRPV1 in the nanomolar range of RvE1, higher concentrations of RvE1 also inhibited TRPA1, possibly through PKC. Collectively, our findings reveal FFAR1 and FFAR4 as key signaling pathways mediating the selective targeting of resolvins to regulate TRPA1 and TRPV1, elucidating endogenous analgesic mechanisms that could be exploited as potential therapeutic targets.
Learn More >Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 ± 6.9 days/month) and severe disability (MIDAS score: 43.0 ± 40.8; HIT-6 score: 60.4 ± 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent ≥ 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now.
Learn More >Besides representing the place where a migraine attack generates, what is the physiological role of peptidergic control of arteriolar caliber within the trigemino-vascular system? Considering that the shared goal of most human CGRP-based neurosensory systems is the protection from an acute threat, especially if hypoxic, what is the end meaning of a migraine attack? In this paper, we have reviewed available evidence on the possible role of the trigemino-vascular system in maintaining cerebral perfusion pressure homeostasis, despite the large physiological fluctuations in intracranial pressure occurring in daily life activities. In this perspective, the migraine attack is presented as the response to a cerebral hypoxic threat consequent to a deranged intracranial pressure control aimed at generating a temporary withdrawal from the environment with limitation of physical activity, a condition required to promote the restoration of cerebral fluids dynamic balance.
Learn More >The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful.
Learn More >Pain is a complex experience, encompassing physiological and psychological components. Amongst the different types of pain, neuropathic pain, resulting from injuries to the peripheral or central nervous system, still constitutes a challenge for researchers and clinicians. Nerve growth factor (NGF) is currently regarded as a key contributor and may serve as a therapeutic target in many types of pain, likely including neuropathic pain. Here, we reviewed the role of NGF in neuropathic pain of peripheral and central origin, also addressing its potential use as a pharmacological target to better help patients dealing with this condition that severely impacts the everyday life. For this, we conducted a search in the databases PubMed and Scopus. Our search resulted in 1103 articles (458 in PubMed and 645 in Scopus). Only articles related to the involvement of NGF in pain or articles that approached its potential use as a target in treatment of pain symptoms were included. Duplicates were eliminated and 274 articles were excluded. After careful analysis, 23 articles were selected for review. Original articles studying the role of NGF in pathology as well as its modulation as a possible therapeutic target were included. We found that NGF is widely regarded as a key player in neuropathic pain and seen as a putative therapeutic target. However, evidence obtained from years of clinical trials highlights the toxic adverse effects of anti-NGF therapeutics, precluding its use in clinical context. Further studies are, thus, needed to improve treatment of chronic neuropathic pain.
Learn More >For millenniums, mindfulness was believed to diminish pain by reducing the influence of self-appraisals of noxious sensations. Today, mindfulness meditation is a highly popular and effective pain therapy that is believed to engage multiple, nonplacebo-related mechanisms to attenuate pain. Recent evidence suggests that mindfulness meditation-induced pain relief is associated with the engagement of unique cortico-thalamo-cortical nociceptive filtering mechanisms. However, the functional neural connections supporting mindfulness meditation-based analgesia remain unknown. This mechanistically focused clinical trial combined functional magnetic resonance imaging with psychophysical pain testing (49°C stimulation and pain visual analogue scales) to identify the neural connectivity supporting the direct modulation of pain-related behavioral and neural responses by mindfulness meditation. We hypothesized that mindfulness meditation-based pain relief would be reflected by greater decoupling between brain mechanisms supporting appraisal (prefrontal) and nociceptive processing (thalamus). After baseline pain testing, 40 participants were randomized to a well-validated, 4-session mindfulness meditation or book-listening regimen. Functional magnetic resonance imaging and noxious heat (49°C; right calf) were combined during meditation to test study hypotheses. Mindfulness meditation significantly reduced behavioral and neural pain responses when compared to the controls. Preregistered (NCT03414138) whole-brain analyses revealed that mindfulness meditation-induced analgesia was moderated by greater thalamus-precuneus decoupling and ventromedial prefrontal deactivation, respectively, signifying a pain modulatory role across functionally distinct neural mechanisms supporting self-referential processing. Two separate preregistered seed-to-seed analyses found that mindfulness meditation-based pain relief was also associated with weaker contralateral thalamic connectivity with the prefrontal and primary somatosensory cortex, respectively. Thus, we propose that mindfulness meditation is associated with a novel self-referential nociceptive gating mechanism to reduce pain.
Learn More >Previously, we observed that B cells and autoantibodies mediated chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome and that complex regional pain syndrome patient antibodies were pronociceptive in fracture mice lacking mature B cells and antibodies (muMT). The current study used a lumbar spinal disk puncture (DP) model of low back pain in wild-type (WT) and muMT mice to evaluate pronociceptive adaptive immune responses. Spinal disks and cords were collected 3 weeks after DP for polymerase chain reaction and immunohistochemistry analyses. Wild-type DP mice developed 24 weeks of hindpaw mechanical allodynia and hyperalgesia, grip weakness, and a conditioned place preference response indicative of spontaneous pain, but pain responses were attenuated or absent in muMT DP mice. Spinal cord expression of inflammatory cytokines, immune cell markers, and complement components were increased in WT DP mice and in muMT DP mice. Dorsal horn immunostaining in WT DP mice demonstrated glial activation and increased complement 5a receptor expressionin spinal neurons. Serum collected from WT DP mice and injected into muMT DP mice caused nociceptive sensitization, as did intrathecal injection of IgM collected from WT DP mice, and IgM immune complexes were observed in lumbar spinal disks and cord of WT DP mice. Serum from WT tibia fracture mice was not pronociceptive in muMT DP mice and vice versa, evidence that each type of tissue trauma chronically generates its own unique antibodies and targeted antigens. These data further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.
Learn More >Previous studies have consistently revealed that both local and systemic inflammations are the key to the onset and progression of osteoarthritis (OA). Thus, anti-inflammatory biologic agents could potentially attenuate the progression of OA. We conducted this meta-analysis to examine the efficacy and safety of ant-inflammatory biologic agents among OA patients.
Learn More >This study aimed to analyze correlations between Self-Report Leeds Assessment of Neuropathic Symptoms (S-LANSS) and PainDETECT with proxies of sensitization, pain-related, or psychological/cognitive variables in coronavirus disease, 2019 (COVID-19) survivors exhibiting post-COVID pain. Demographic, clinical, psychological, cognitive, sensitization-associated symptoms, and health-related quality of life were collected in 146 survivors with post-COVID pain. The PainDETECT and S-LANSS questionnaires were used for assessing neuropathic pain-related symptoms. Patients were assessed with a mean of 18.8 (SD 1.8) months after hospitalization. Both questionnaires were positively associated with pain intensity ( < 0.05), anxiety (PainDETECT < 0.05; S-LANSS < 0.01), sensitization-associated symptoms ( < 0.01), catastrophism ( < 0.01), and kinesiophobia ( < 0.01) and negatively associated with quality of life (PainDETECT < 0.05; S-LANSS < 0.01). Depressive levels were associated with S-LANSS ( < 0.05) but not with PainDETECT. The stepwise regression analyses revealed that 47.2% of S-LANSS was explained by PainDETECT (44.6%), post-COVID pain symptoms duration (1.7%), and weight (1.1%), whereas 51.2% of PainDETECT was explained by S-LANSS (44.6%), sensitization-associated symptoms (5.4%), and anxiety levels (1.2%). A good convergent association between S-LANSS and PainDETECT was found. Additionally, S-LANSS was associated with symptom duration and weight whereas PainDETECT was associated with sensitization-associated symptoms and anxiety levels, suggesting that the two questionnaires evaluate different aspects of the neuropathic pain spectrum in post-COVID pain patients.
Learn More >Neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases quality of life (QOL) and is often refractory to available therapies. Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief. One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) proteins in uninjured C fibers and dorsal root ganglia causing neuronal excitability. Recent studies have found up-regulation of TRPV 1 proteins after SCI.
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