Advanced oxidation protein products activated TRPA1 in a neuropathic multiple sclerosis model.

Relapsing-remitting multiple sclerosis (RRMS), is characterized by increased oxidative compound production and neuroinflammation, accompanied by neuropathic pain and anxiety. Activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox) generates oxidative stress by-products that induce nociception and anxiety-like behaviors by transient receptor potential ankyrin 1 (TRPA1) activation in the relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model. Nox activation stimulates myeloperoxidase (MPO), producing advanced oxidation protein products (AOPPs).

Activation of peripheral NOP receptors reduces periorbital mechanical allodynia evoked by CGRP in mice.

Background And Purpose: Migraine is a neurovascular disorder largely mediated by calcitonin gene-related peptide (CGRP). This study explores the role of the nociceptin/orphanin FQ (N/OFQ)-N/OFQ receptor (NOP) system in CGRP-induced periorbital mechanical allodynia (PMA) in mice.

Experimental Approach: Male or female wild type (NOP(+/+)) and NOP receptor knockout (NOP(-/-)) mice and CD-1 mice were used.

Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo.

The transient receptor potential ankyrin 1 (TRPA1) channel has been extensively studied as a potential therapeutic target for the treatment of different pain types, with better efficacy and safety profiles compared to current therapies. Because TRPA1 is implicated in different pathophysiological processes, selective antagonists of this channel could provide therapeutic benefits beyond pain relief. In this study, we report the design and synthesis of a novel series of carboxamide derivatives incorporating an isoxazole moiety, which were evaluated for their ability to inhibit TRPA1-mediated signalling.

Evidence-based guidelines for the pharmacological treatment of migraine, summary version.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions.

Evidence-based guidelines for the pharmacological treatment of migraine.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions.

Pain Signaling by GPCRs and RTKs.

Chronic pain is common and debilitating, yet is inadequately treated by current therapies, which can have life-threatening side effects. Treatments targeting G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), key pain mediators, often fail in clinical trials for unknown reasons. Here, we discuss the recent evidence that GPCRs and RTKs generate sustained signals from multiprotein signaling complexes or signalosomes in intracellular compartments to control chronic pain.

Characterisation of periorbital mechanical allodynia in the reserpine-induced fibromyalgia model in mice: The role of the Schwann cell TRPA1/NOX1 signalling pathway.

Fibromyalgia (FM) is a complex and multifaceted condition characterized by a range of clinical symptoms, including widespread pain and a strong association with migraine headaches. Recent findings have underscored the role of oxidative stress and transient receptor potential ankyrin 1 (TRPA1) channel in migraine and FM. However, the precise mechanisms underlying the comorbidity between migraine and FM are unclear.

An evolving machine-learning-based algorithm to early predict response to anti-CGRP monoclonal antibodies in patients with migraine.

Background: The present study aimed to determine whether machine-learning (ML)-based models can predict 3-, 6, and 12-month responses to the monoclonal antibodies (mAbs) against the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRPmAbs) in patients with migraine using early predictors (up to one month) and to create an evolving prediction tool.

Methods: In this prospective cohort study data from patients with migraine who had received anti-CGRP mAbs for 12 months were collected. Demographic and monthly clinical variables were collected, including monthly headache days (MHDs), days with acute medication use, number of analgesics and Headache Impact Test-6.

Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.

Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain.

Outcomes, unmet needs, and challenges in the management of patients who withdraw from anti-CGRP monoclonal antibodies: A prospective cohort study.

Background: The anti-calcitonin gene-related peptide (CGRP), or its receptor (CGRP/R) monoclonal antibodies (mAbs), offer targeted, effective, and tolerated drugs for migraine. However, about 25% of patients fail to achieve a clinically meaningful response, usually leading to discontinuation. These patients often have a lengthy migraine history and multiple prior preventive treatment failures, resulting in limited therapeutic options.

Schwann cell transient receptor potential ankyrin 1 (TRPA1) ortholog in zebrafish larvae mediates chemotherapy-induced peripheral neuropathy.

Background And Purpose: The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae.

Experimental Approach: We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours.

Impact of duration of chronic migraine on long-term effectiveness of monoclonal antibodies targeting the calcitonin gene-related peptide pathway-A real-world study.

Objective: We assessed whether the effectiveness of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway changes according to the duration of chronic migraine (CM) over 12 months.

Background: In most patients, CM is a progressive disease starting with episodic migraine. Longer CM duration might be associated with more difficult treatment, probably because the mechanisms underlying chronicization are strengthened.

Schwann cell TRPA1 elicits reserpine-induced fibromyalgia pain in mice.

Background And Purpose: Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear.

Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients.

Background/objectives: Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients.

Methods: Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed.

The first interim analysis of Italian patients enrolled in the real-world, Pan-European, prospective, observational, phase 4 PEARL study of fremanezumab effectiveness.

Introduction: In 2020, the Italian Medicines Agency (AIFA) approved the reimbursement of calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs), including fremanezumab, in patients with a Migraine Disability Assessment Scale (MIDAS) score ≥ 11, with prescription renewals for up to 12 months in patients with ≥ 50% reduction in MIDAS score at Months 3 and 6. In this sub-analysis of the Pan-European Real Life (PEARL) study, we provide real-world data on fremanezumab use in Italian routine clinical practice (EUPAS35111).

Methods: This first interim analysis for Italy was conducted when 300 enrolled adult patients with episodic or chronic migraine (EM, CM) completed 6 months of treatment with fremanezumab.

Long-Term Treatment Over 52 Weeks with Monthly Fremanezumab in Drug-Resistant Migraine: A Prospective Multicenter Cohort Study.

Background: Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up.

Objective: We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine.

Methods: This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures.

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches.

Ion channels play a crucial role in a wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family of channels has emerged as a promising therapeutic target due to its involvement in several stages of cancer development and dissemination. TRP channels are expressed in a large variety of cells and tissues, and by increasing cation intracellular concentration, they monitor mechanical, thermal, and chemical stimuli under physiological and pathological conditions.

Patterns of anti-CGRP mAbs use and variation of triptan consumption following treatment initiation: A descriptive drug utilization study in the Tuscany region, Italy.

Objective: To describe the pattern of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation.

Background: Given the recent commercialization of anti-CGRP mAbs as migraine preventive medications, real-world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited.

Methods: A retrospective, descriptive, cohort study on the real-world utilization of anti-CGRP mAbs was performed using the population-based regional administrative database of Tuscany.

Migraine Treatment: Towards New Pharmacological Targets.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP).

Retreating migraine patients in the second year with monoclonal antibodies anti-CGRP pathway: the multicenter prospective cohort RE-DO study.

Background: The outcome of migraine patients retreated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (anti-CGRP) or its receptor (anti-CGRPr) is not completely known.

Methods: This multicentric prospective observational cohort study assessed monthly migraine days (MMDs), migraine acute medication intake (MAMI), and HIT-6 at baseline, after 90-112 days (Rev-1), after 84-90 days since Rev-1 (Rev-2) and 30 days after the last injection of anti-CGRP/CGRPr mAbs (Year-end), in the first and the second year after a discontinuation period.

Results: We enrolled 226 patients (79.

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice.

: Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS.

Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhoea.

Research Question: Women with endometriosis are frequently affected by headache. How many of these have a clear diagnosis of migraine? Are the different forms of migraine related to the phenotypes and/or characteristics of endometriosis?

Design: This was a prospective nested case-control study. A consecutive series of 131 women with endometriosis who attended the endometriosis clinic were enrolled and examined for the presence of headache.

Neuronal and non-neuronal TRPA1 as therapeutic targets for pain and headache relief.

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, has a major role in different types of pain. TRPA1 is primarily localized to a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of nociceptors produces and releases the neuropeptide substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammation.