Publications by authors named "Pierangelo Geppetti"

173 Publications

COVID-19 pneumonia during long-term migraine prophylaxis with fremanezumab: a case report.

Intern Emerg Med 2021 Jun 12. Epub 2021 Jun 12.

Headache Center and Clinical Pharmacology, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50139, Florence, Italy.

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http://dx.doi.org/10.1007/s11739-021-02787-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196929PMC
June 2021

Migraine during COVID-19: Data from Second Wave Pandemic in an Italian Cohort.

Brain Sci 2021 Apr 10;11(4). Epub 2021 Apr 10.

Applied Neurophysiology and Pain Unit, SMBNOS Department, Bari Aldo Moro University, 70121 Bari, Italy.

Objectives: The study aims to assess the impact of the second COVID-19 pandemic wave on migraine characteristics.

Methods: This is an observational cross-sectional study conducted on migraine patients previously interviewed during the first Italian pandemic outbreak. A second structured telephone interview was conducted between 20 November 2020 and 18 January 2021. We compared migraine characteristics among T0 (before pandemic), T1 (during the first pandemic phase), and T2 (during the second pandemic phase).

Results: Among the 433 patients interviewed during the first pandemic phase, 304 cases were finally considered. One hundred forty-eight patients had a control visit between March 2020 and December 2020, 120 had an in-person visit, 14 by phone, the remainder used telemedicine software provided by the hospital. Frequency of headache, number of symptomatic drugs and headache intensity worsened during T2, compared to T0 and T1, especially in episodic migraine. Headache intensity increased relating to the negative emotional impact of the pandemic. Migraine management during the pandemic did not influence the clinical outcome.

Conclusion: The prolongation of the pandemic seems to have a negative impact on migraine evolution. The arousal and negative psychological behavior toward the COVID-19 outbreak seem to worsen migraine.
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http://dx.doi.org/10.3390/brainsci11040482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070557PMC
April 2021

The Role of TRPA1 in Skin Physiology and Pathology.

Int J Mol Sci 2021 Mar 17;22(6). Epub 2021 Mar 17.

Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, 50139 Florence, Italy.

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, acts as 'polymodal cellular sensor' on primary sensory neurons where it mediates the peripheral and central processing of pain, itch, and thermal sensation. However, the TRPA1 expression extends far beyond the sensory nerves. In recent years, much attention has been paid to its expression and function in non-neuronal cell types including skin cells, such as keratinocytes, melanocytes, mast cells, dendritic cells, and endothelial cells. TRPA1 seems critically involved in a series of physiological skin functions, including formation and maintenance of physico-chemical skin barriers, skin cells, and tissue growth and differentiation. TRPA1 appears to be implicated in mechanistic processes in various immunological inflammatory diseases and cancers of the skin, such as atopic and allergic contact dermatitis, psoriasis, bullous pemphigoid, cutaneous T-cell lymphoma, and melanoma. Here, we report recent findings on the implication of TRPA1 in skin physiology and pathophysiology. The potential use of TRPA1 antagonists in the treatment of inflammatory and immunological skin disorders will be also addressed.
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http://dx.doi.org/10.3390/ijms22063065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002674PMC
March 2021

Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain.

Cancer Res 2021 Jun 26;81(12):3387-3401. Epub 2021 Mar 26.

Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.

Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260461PMC
June 2021

Oxidative stress mediates thalidomide-induced pain by targeting peripheral TRPA1 and central TRPV4.

BMC Biol 2020 12 14;18(1):197. Epub 2020 Dec 14.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.

Background: The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models.

Results: Here, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia.

Conclusions: Targeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.
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http://dx.doi.org/10.1186/s12915-020-00935-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737339PMC
December 2020

Investigating the Effects of COVID-19 Quarantine in Migraine: An Observational Cross-Sectional Study From the Italian National Headache Registry (RICe).

Front Neurol 2020 10;11:597881. Epub 2020 Nov 10.

Applied Neurophysiology and Pain Unit, Scienze Mediche di Base, Neuroscienze e Organi di Senso Department, Bari Aldo Moro University, Bari, Italy.

Previous studies during SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects, such as post-traumatic stress symptoms, confusion, and anger. These conditions may affect the course of many diseases, including migraine. Although it is possible that the quarantine measures for the current COVID-19 pandemic affect migraine burden, no information is currently available on this issue. In this study, we aimed to: (1) explore the possible changes in migraine frequency, severity, and days with acute medication intake during quarantine period; (2) evaluate possible differences in migraine outcomes in consideration of lifestyle changes, emotions, pandemic diffusion, and COVID-19 infection. We interviewed patients who were included in the observational Italian Headache Registry (Registro Italiano Cefalee, RICE), retrospectively collecting information on main headache features, lifestyle factors, emotions, individual infection status, and perception of COVID-19 for 2 months before (pre-quarantine) and after the beginning of the quarantine (quarantine). Inclusion criteria were: age > 18, diagnosis of migraine without aura, migraine with aura and chronic migraine, last in-person visit more than 3 months preceding the beginning of quarantine. A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency (9.42 ± 0.43 days with headache vs. 8.28 ± 0.41) and intensity (6.57 ± 0.19 vs. 6.59 ± 0.21) during the quarantine, compared to pre-quarantine. There was a correlation between improvement and number of days of stay-at-home. When results were stratified for geographic area, we found a tendency toward worsening of headache frequency in northern Italy. Disgust regarding viral infection corresponded to a minor improvement in migraine. Migraine patients showed a mild improvement of migraine features, probably attributable to resilient behavior toward pandemic distress. Disgust regarding the contagion whereas potentially favoring defensive behavior, could potentially worsen migraine. The spontaneous limitation of migraine burden during quarantine could favor patient follow-up via the use of telemedicine visits, reliable diaries, and frequent remote contacts.
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http://dx.doi.org/10.3389/fneur.2020.597881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683429PMC
November 2020

What is changing in chronic migraine treatment? An algorithm for onabotulinumtoxinA treatment by the Italian chronic migraine group.

Expert Rev Neurother 2020 12 30;20(12):1275-1286. Epub 2020 Sep 30.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome, Italy.

Introduction: OnabotulinumtoxinA (OBT-A) and monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway are two of the few treatments that ameliorate chronic migraine (CM) in randomized controlled trials and real-life studies. Separate clinical practice guidelines have been developed for the management of CM with OBT-A or CGRP-targeting mAbs.

Areas Covered: Considering the concomitant availability of OBT-A and CGRP-targeting mAbs as therapeutic treatment options, Italian migraine experts reviewed the evidence supporting the efficacy of OBT-A and CGRP-targeting mAbs in CM in order to rationalize the management of CM patients treated with OBT-A. Experts addressed everyday practice needs to shape the optimal pharmacological management by balancing adherence to regulatory indications, ethical considerations, and clinical expertise. Considering the remarkable challenge of improving the health and quality of life of patients with CM, even partial improvements may be clinically meaningful, particularly for those who are resistant or intolerant to oral migraine treatments.

Expert Opinion: In this collaborative effort, we propose a treatment algorithm that integrates the relevant aspects of managing patients with CM to provide ready-to-use practical guidance regarding the appropriate use of OBT-A.
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http://dx.doi.org/10.1080/14737175.2020.1825077DOI Listing
December 2020

Medicines for headache before and during pregnancy: a retrospective cohort study (ATENA study).

Neurol Sci 2021 May 23;42(5):1895-1921. Epub 2020 Sep 23.

Headache Centre, Careggi University Hospital, Florence, Italy.

Objective: To investigate headache treatment before and during pregnancy.

Background: Most headaches in pregnancy are primary disorders. Headaches are likely to ameliorate during pregnancy, although they may also begin or worsen. Most headache medications should be avoided during pregnancy because of potential fetal risks. However, only scarce evidence on headache drug consumption during pregnancy is available.

Design: ATENA was a retrospective, self-administered questionnaire-based, cohort study on women in either pregnancy or who have just delivered and reporting headache before and/or during pregnancy.

Results: Out of 271 women in either pregnancy or who have just delivered, 100 (37%) reported headache before and/or during pregnancy and constituted our study sample. Before pregnancy, the attitude toward the use of symptomatic drugs was characterized by both a strong focus on their safety and the willingness to avoid possible dependence from them. Compared to the year before, pregnancy led to changes in behavior and therapeutic habits as shown by a higher proportion of patients looking for information about drugs (44/100 [44%] vs. 36/100 [36%]) and a lower proportion of those treating headache attacks (88/100 [88%] vs. 52/100 [52%]) and by a lower use of nonsteroidal anti-inflammatory drugs (68/100 [68%] vs. 5/100 [5%]) and a much higher use of paracetamol (33/100 [33%] vs. 95/100 [95%]).

Conclusions: Pregnancy changes how women self-treat their headache, and leads to search for information regarding drug safety, mostly due to the perception of fetal risk of drugs. Healthcare providers have to be ready to face particular needs of pregnant women with headache.
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http://dx.doi.org/10.1007/s10072-020-04702-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043957PMC
May 2021

TRPA1 as a therapeutic target for nociceptive pain.

Expert Opin Ther Targets 2020 10 11;24(10):997-1008. Epub 2020 Sep 11.

Department of Health Sciences, Clinical Pharmacology Unit, University of Florence , Florence, Italy.

Introduction: Chronic pain affects approximatively 30-50% of the population globally. Pathologies such as migraine, diabetic neuropathy, nerve injury and treatment with chemotherapeutic agents, can induce chronic pain. Members of the transient receptor potential (TRP) channels, including the TRP ankyrin 1 (TRPA1), have a major role in pain.

Areas Covered: We focus on TRPA1 as a therapeutic target for pain relief. The structure, localization, and activation of the channel and its implication in different pathways to signal pain are described. This paper underlines the role of pharmacological interventions on TRPA1 to reduce pain in numerous pain conditions. We conducted a literature search in PubMed up to and including July 2020.

Expert Opinion: Our understanding of the molecular mechanisms underlying the sensitization of central and peripheral nociceptive pathways is limited. Preclinical evidence indicates that, in murine models of pain diseases, numerous mechanisms converge on the pathway that encompasses oxidative stress and Schwann cell TRPA1 to sustain chronic pain. Programs to identify and develop treatments to attenuate TRPA1-mediated chronic pain have emerged from this knowledge. Antagonists explored as a novel class of analgesics have a new and promising target in the TRPA1 expressed by peripheral glial cells.
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http://dx.doi.org/10.1080/14728222.2020.1815191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610834PMC
October 2020

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice.

Cell Death Dis 2020 08 15;11(8):633. Epub 2020 Aug 15.

Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil.

Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.
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http://dx.doi.org/10.1038/s41419-020-02863-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429961PMC
August 2020

Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.

Neurol Sci 2021 Mar 20;42(3):987-994. Epub 2020 Jul 20.

NEUROFARBA Department, Toxicology Unit, Careggi University Hospital, University of Florence, Florence, Italy.

Objectives: A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.

Methods: A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.

Results: Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed.

Conclusion: LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.
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http://dx.doi.org/10.1007/s10072-020-04602-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870632PMC
March 2021

SARS-CoV-2 and COVID-19: From the Bench to the Bedside.

Physiol Rev 2020 10 4;100(4):1455-1466. Epub 2020 Jun 4.

Department of Health Sciences, Section of Anesthesiology, Intensive Care and Pain Medicine, University of Florence, Florence, Italy; Department of Anesthesiology and Intensive Care, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Intensive Care Unit and Regional ECMO Referral Centre, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.

First isolated in China in early 2020, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for the ongoing pandemic of Coronavirus Disease 2019 (COVID-19). The disease has been spreading rapidly across the globe, with the largest burden falling on China, Europe, and the United States. COVID-19 is a new clinical syndrome, characterized by respiratory symptoms with varying degrees of severity, from mild upper respiratory illness to severe interstitial pneumonia and acute respiratory distress syndrome, aggravated by thrombosis in the pulmonary microcirculation. Three main phases of disease progression have been proposed for COVID-19: an early infection phase, a pulmonary phase, and a hyperinflammation phase. Although current understanding of COVID-19 treatment is mainly derived from small uncontrolled trials that are affected by a number of biases, strong background noise, and a litany of confounding factors, emerging awareness suggests that drugs currently used to treat COVID-19 (antiviral drugs, antimalarial drugs, immunomodulators, anticoagulants, and antibodies) should be evaluated in relation to the pathophysiology of disease progression. Drawing upon the dramatic experiences taking place in Italy and around the world, here we review the changes in the evolution of the disease and focus on current treatment uncertainties and promising new therapies.
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http://dx.doi.org/10.1152/physrev.00020.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347954PMC
October 2020

Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis.

Sci Rep 2020 05 25;10(1):8632. Epub 2020 May 25.

Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.

Pain evoked by visceral inflammation is often 'referred' to the somatic level. Transient receptor potential ankyrin 1 (TRPA1) has been reported to contribute to visceral pain-like behavior in dextran sulfate sodium (DSS)-evoked colitis. However, the role of TRPA1 in somatic component of hypersensitivity due to visceral inflammation is unknown. The present study investigated the role of TRPA1 in colitis-evoked mechanical hypersensitivity at the somatic level. Colitis was induced in mice by adding DSS to drinking water for one week. Control and DSS-treated mice were tested for various parameters of colitis as well as mechanical pain sensitivity in abdominal and facial regions. DSS treatment caused mechanical hypersensitivity in the abdominal and facial skin. Pharmacological blockade or genetic deletion of TRPA1 prevented the colitis-associated mechanical hypersensitivity in the abdominal and facial skin areas although the severity of colitis remained unaltered. DSS treatment increased expression of TRPA1 mRNA in cultured dorsal root ganglion (DRG) neurons, but not trigeminal ganglion neurons, and selectively enhanced currents evoked by the TRPA1 agonist, allyl isothiocyanate, in cultured DRG neurons. Our findings indicate that the TRPA1 channel contributes to colitis-associated mechanical hypersensitivity in somatic tissues, an effect associated with upregulation of TRPA1 expression and responsiveness in DRG nociceptors.
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http://dx.doi.org/10.1038/s41598-020-65618-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248095PMC
May 2020

Macrophages and Schwann cell TRPA1 mediate chronic allodynia in a mouse model of complex regional pain syndrome type I.

Brain Behav Immun 2020 08 18;88:535-546. Epub 2020 Apr 18.

Department of Health Sciences, University of Florence, 50139 Florence, Italy; Graduate Program in Health Sciences, University of the Extreme South of Santa Catarina (Unesc), 88006-000 Criciúma (SC), Brazil; Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM), 97105-900 Santa Maria (RS), Brazil. Electronic address:

Complex regional pain syndrome type I (CRPS-I) is characterized by intractable chronic pain. Poor understanding of the underlying mechanisms of CRPS-I accounts for the current unsatisfactory treatment. Antioxidants and antagonists of the oxidative stress-sensitive channel, the transient receptor potential ankyrin 1 (TRPA1), have been found to attenuate acute nociception and delayed allodynia in models of CRPS-I, evoked by ischemia and reperfusion (I/R) of rodent hind limb (chronic post ischemia pain, CPIP). However, it is unknown how I/R may lead to chronic pain mediated by TRPA1. Here, we report that the prolonged (day 1-15) mechanical and cold allodynia in the hind limb of CPIP mice was attenuated permanently in Trpa1 mice and transiently after administration of TRPA1 antagonists (A-967079 and HC-030031) or an antioxidant (α-lipoic acid). Indomethacin treatment was, however, ineffective. We also found that I/R increased macrophage (F4/80 cell) number and oxidative stress markers, including 4-hydroxynonenal (4-HNE), in the injured tibial nerve. Macrophage-deleted MaFIA (Macrophage Fas-Induced Apoptosis) mice did not show I/R-evoked endoneurial cell infiltration, increased 4-HNE and mechanical and cold allodynia. Furthermore, Trpa1 mice did not show any increase in macrophage number and 4-HNE in the injured nerve trunk. Notably, in mice with selective deletion of Schwann cell TRPA1 (Plp1-Cre;Trpa1 mice), increases in macrophage infiltration, 4-HNE and mechanical and cold allodynia were attenuated. In the present mouse model of CRPS-I, we propose that the initial oxidative stress burst that follows reperfusion activates a feed forward mechanism that entails resident macrophages and Schwann cell TRPA1 of the injured tibial nerve to sustain chronic neuroinflammation and allodynia. Repeated treatment one hour before and for 3 days after I/R with a TRPA1 antagonist permanently protected CPIP mice against neuroinflammation and allodynia, indicating possible novel therapeutic strategies for CRPS-I.
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http://dx.doi.org/10.1016/j.bbi.2020.04.037DOI Listing
August 2020

Ion Channel Pharmacology for Pain Modulation.

Handb Exp Pharmacol 2019 ;260:161-186

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.

A large series of different ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including pain. Among these channels, the voltage gated calcium channels (VGCC) are inhibited by drugs for the treatment of migraine, neuropathic pain or intractable pain. Transient receptor potential (TRP) channels are emerging as important pain transducers as they sense low pH media or oxidative stress and other mediators and are abundantly found at sites of inflammation or tissue injury. Low pH may also activate acid sensing ion channels (ASIC) and mechanical forces stimulate the PIEZO channels. While potent agonists of TRP channels due to their desensitizing action on pain transmission are used as topical applications, the potential of TRP antagonists as pain therapeutics remains an exciting field of investigation. The study of ASIC or PIEZO channels in pain signaling is in an early stage, whereas antagonism of the purinergic P2X channels has been reported to provide beneficial effects in chronic intractable cough. The present chapter covers these intriguing channels in great detail, highlighting their diverse mechanisms and broad potential for therapeutic utility.
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http://dx.doi.org/10.1007/164_2019_336DOI Listing
January 2020

Epidemiology and determinants of chronic migraine: A real-world cohort study, with nested case-control analysis, in primary care in Italy.

Cephalalgia 2020 04 19;40(5):461-469. Epub 2019 Nov 19.

Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.

Background: The proper identification of chronic migraine is one of the mainstays for general practitioners. This study therefore aims to assess the epidemiology and determinants of chronic migraine in primary care in Italy by testing five operational case definition algorithms.

Methods: Five case definition algorithms defining chronic migraine were developed to estimate the prevalence and incidence rate of chronic migraine in the Health Search database. For each algorithm, we conducted a nested case-control analysis to quantify the level of association between certain determinants and incident cases of chronic migraine.

Results: Considering a cohort of 1,091,032 patients (52% were females), the prevalence rate of chronic migraine increased from the first to the fifth case definition algorithm ranging from 0.03 to 0.28%. No 95% confidence interval overlapped the others, and every confidence interval reliably maintained 2% precision. Incidence rates showed a growing trend (0.008-0.056 per 100,000 person-years) as well. All case definition algorithms were able to capture sex (i.e. female) and nonsteroidal anti-inflammatory drug (NSAID) overuse as statistically significant determinants of incident cases of chronic migraine. Depression was associated with a statistically significant increase of incidence rate of chronic migraine only for two case definition algorithms.

Conclusion: Our findings show that prevalence and incidence rate of chronic migraine are underestimated when compared with current literature. On the other hand, we found acceptable correctness of chronic migraine definition in the light of the association with well-known determinants.
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http://dx.doi.org/10.1177/0333102419889351DOI Listing
April 2020

Criterion-related validity in a sample of migraine outpatients: the diagnostic criteria for psychosomatic research.

CNS Spectr 2020 08 28;25(4):545-551. Epub 2019 Oct 28.

Department of Health Sciences, University of Florence, Florence, Italy.

Objective: The Diagnostic Criteria for Psychosomatic Research (DCPR) are those of psychosomatic syndromes that did not find room in the classical taxonomy. More recently, the DCPR were updated, called DCPR-revised (DCPR-R). The present study was conducted to test the criterion-related validity of the DCPR-R.

Methods: Two hundred consecutive subjects were enrolled at the Headache Center of Careggi University Hospital (Italy): 100 subjects had a diagnosis of chronic migraine (CM) and 100 had a diagnosis of episodic migraine (EM). Participants received a clinical assessment, which included the DCPR-revised Semi-Structured Interview (DCPR-R SSI), the Structured Clinical Interview for DSM-5 (SCID-5), and the psychosocial index (PSI).

Results: Forty-seven subjects (23.5%) had at least one DSM-5 diagnosis: major depressive disorder (8.5%; n = 17) and agoraphobia (7.5%; n = 15) were the most frequent. One hundred and ten subjects (55%) reported a DCPR-R diagnosis: allostatic overload (29%; n = 58) and type A behavior (10.5%; n = 21) were the most frequent. When the incremental validity of the DCPR system over the DSM system was tested using PSI subscales as the criterion variable, the DCPR-R increased up to 0.11-0.24 the amount of explained variance. Subjects with at least one DCPR-R diagnosis showed lower PSI well-being scores (p = .001), higher PSI stress scores (p < .001), and higher PSI psychological distress scores (p = .008) than subjects without a DCPR-R diagnosis.

Conclusion: The DCPR-R showed a good criterion-related validity in migraine outpatients. Thus, they might be implemented, together with the DSM-5, in the assessment of migraine subjects.
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http://dx.doi.org/10.1017/S1092852919001536DOI Listing
August 2020

Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice.

J Clin Invest 2019 12;129(12):5424-5441

Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.

Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia, and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1-dependent (NOX1-dependent) production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1-/- or Plp1-Cre Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small-fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.
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http://dx.doi.org/10.1172/JCI128022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877331PMC
December 2019

The Role of β-Blockers in Melanoma.

J Neuroimmune Pharmacol 2020 03 3;15(1):17-26. Epub 2019 Sep 3.

Headache Centre, Careggi University Hospital, Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.

Melanoma is one of the most aggressive and less chemotherapy-responsive human cancers, representing a major public health issue worldwide. The early diagnosis still represents the best approach in order to reduce mortality, especially in advanced stages. Preclinical evidence, collected through several in vitro and in vivo models, has been accumulating about the pathophysiological involvement of β-adrenoceptors in melanoma progression. This involvement has been paralleled by the evidence that drugs blocking β-adrenoceptors (β-blockers) may have a relevant role in the treatment of melanoma and in the prevention of its progression. β-blockers are a class of drugs extensively used in clinical practice, not limited to cardiovascular therapeutics. Evidence collected through retrospective and prospective observational studies suggests that treatment with β-blockers, mainly propranolol, is able to delay melanoma progression. Although conclusive evidence is still lacking, current knowledge proposes β-blockers as an opportunity for antitumor treatment in melanoma. Clinical trials are needed in order to prove their claimed efficacy. Graphical Abstract.
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http://dx.doi.org/10.1007/s11481-019-09876-9DOI Listing
March 2020

Dacarbazine alone or associated with melanoma-bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice.

Int J Cancer 2020 05 8;146(10):2797-2809. Epub 2019 Oct 8.

Graduate Program in Health Science, University of the Extreme South of Santa Catarina-Unesc, Criciúma, Brazil.

Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.
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http://dx.doi.org/10.1002/ijc.32648DOI Listing
May 2020

β -Adrenoceptor as a potential immuno-suppressor agent in melanoma.

Br J Pharmacol 2019 07 9;176(14):2509-2524. Epub 2019 May 9.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer University Children's Hospital, Florence, Italy.

Background And Purpose: Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β -adrenoceptors have been identified as new targets in treating melanoma. Recently, β -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β -adrenoceptors in immune-tolerance regulation.

Experimental Approach: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β - or β -adrenoceptors were used.

Key Results: Only β -, but not β -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes.

Conclusions And Implications: Our data suggest that β -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth.

Linked Articles: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592854PMC
July 2019

The acyl-glucuronide metabolite of ibuprofen has analgesic and anti-inflammatory effects via the TRPA1 channel.

Pharmacol Res 2019 04 19;142:127-139. Epub 2019 Feb 19.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy. Electronic address:

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation site for the ligand. Local administration of ibuprofen-acyl glucuronide, but not ibuprofen, in the mouse hind paw attenuated nociception by AITC and other TRPA1 agonists and the early nociceptive response (phase I) to formalin. Systemic ibuprofen-acyl glucuronide and ibuprofen, but not indomethacin, reduced phase I of the formalin response. Carrageenan-evoked allodynia in mice was reduced by local ibuprofen-acyl glucuronide, but not by ibuprofen, whereas both drugs attenuated PGE levels. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited the release of IL-8 evoked by AITC from cultured bronchial epithelial cells. The reactive ibuprofen metabolite selectively antagonizes TRPA1, suggesting that this novel action of ibuprofen-acyl glucuronide might contribute to the analgesic and anti-inflammatory activities of the parent drug.
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http://dx.doi.org/10.1016/j.phrs.2019.02.019DOI Listing
April 2019

Migraine-provoking substances evoke periorbital allodynia in mice.

J Headache Pain 2019 Feb 14;20(1):18. Epub 2019 Feb 14.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.

Background: Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area.

Methods: Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections.

Results: Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E (PGE) and prostacyclin (PGI), but not PGF evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H, PGE (EP), and PGI (IP) receptors, respectively.

Conclusions: The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE, PGI), or do not provoke (VIP and PGF), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.
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http://dx.doi.org/10.1186/s10194-019-0968-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734434PMC
February 2019

Changes in grey matter volume and functional connectivity in cluster headache versus migraine.

Brain Imaging Behav 2020 Apr;14(2):496-504

Headache Centre, Careggi University Hospital, Department of Health Sciences, University of Florence, Florence, Italy.

Cluster headache (CH) shows a more severe clinical picture than migraine (Mig). We tested whether brain changes can explain such difference. Multimodal MRI was acquired in attack-free patients with CH (n = 12), Mig (n = 13) and in normal controls (NC, n = 13). We used FSL for MRI data analysis and nonparametric permutation testing for voxelwise analyses (p < 0.01, corrected). CH showed lower grey matter (GM) volume, compared to Mig and NC, in frontal cortex regions (inferior frontal gyrus and frontal pole [FP], respectively) and, only compared to Mig, in lateral occipital cortex (LOC). Functional connectivity (FC) of CH was higher than Mig and NC within working memory and executive control networks and, only compared to Mig, between cerebellar and auditory language comprehension networks. In the attack-free state, the CH brain seems to be characterized by: (i) GM volume decrease, compared to both Mig and NC, in pain modulation regions (FP) and, only with respect to Mig, in a region of visual processing modulation during pain and working memory (LOC); (ii) increased FC at short range compared to both Mig and NC and at long range only with respect to Mig, in key cognitive networks, likely due to maladaptation towards more severe pain experience.
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http://dx.doi.org/10.1007/s11682-019-00046-2DOI Listing
April 2020

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine.

J Headache Pain 2019 Feb 13;20(1):15. Epub 2019 Feb 13.

Department of Clinical and Molecular Medicine, Regional Referral Headache Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy.

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting.

Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version.

Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity.

Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.
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http://dx.doi.org/10.1186/s10194-019-0966-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734365PMC
February 2019

TRPA1 mediates the antinociceptive properties of the constituent of Crocus sativus L., safranal.

J Cell Mol Med 2019 03 12;23(3):1976-1986. Epub 2019 Jan 12.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.

Safranal, contained in Crocus sativus L., exerts anti-inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 (TRPA1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA1, but not the TRP vanilloid 1 and 4 channels (TRPV1 and TRPV4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion (DRG) neurons. Genetic deletion or pharmacological blockade of TRPA1 attenuated safranal-evoked release of calcitonin gene-related peptide (CGRP) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA1-dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate (TRPA1 agonist), but not that of capsaicin (TRPV1 agonist) or GSK1016790A (TRPV4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA1 channel.
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http://dx.doi.org/10.1111/jcmm.14099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378183PMC
March 2019

Correction to: Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial.

J Headache Pain 2018 12 18;19(1):120. Epub 2018 Dec 18.

Neurophysiology and Pain Unit, University of Bari Aldo Moro, Bari, Italy.

Following publication of the original article [1], the authors notified us o that the Table 1 citation within the legend was not presented as initially requested.
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http://dx.doi.org/10.1186/s10194-018-0949-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755543PMC
December 2018

Distinct mechanisms underlying local antinociceptive and pronociceptive effects of natural alkylamides from Acmella oleracea compared to synthetic isobutylalkyl amide.

Fitoterapia 2018 Nov 7;131:225-235. Epub 2018 Nov 7.

Department of Pharmacology, Federal University of Parana, Curitiba, Brazil. Electronic address:

Acmella oleracea (jambu), is used as ingredient for food and in folk medicine to relief toothache. Jambu edible flowers are rich in alkylamides, mainly spilanthol, which are responsible to evoke chemesthetic sensations. This study aimed to investigate the local effects promoted by the intraplantar injection of the hexanic fraction (HF) rich in alkylamides from jambu flowers and compare to synthetic isobutylalkyl amide (IBA). Swiss male mice were intraplantarly administrated with HF and IBA (0.1-30 μg/20 μL), and the underlying mechanisms associated to the antinociceptive (0.1 μg) and pronociceptive (30 μg) effects were evaluated in chemical and sensorial tests. HF and IBA at 0.1 μg promoted analgesia in neurogenic and inflammatory phases of formalin test, against glutamate-induced nociception and independent of the activation of endogenous opioidergic system and dependent of TRPV1 modulation, whereas only HF reduced both nociception and mast cell degranulation in hindpaw induced by compound 48/80. However, both potentiated the TRPA1-mediated nociception. In contrast, HF and IBA (30 μg)-evoked nociceptive behaviors were reduced by the activation of opioidergic system, by TRPA1 antagonist and TRP nociceptive fibers desensitization. In addition, 30 μg IBA-evoked nociception by activation of TRPV1, and 30 μg HF by mast cell degranulation. Furthermore, on the contrary of IBA, HF elevated both mechanical and thermal paw threshold. Altogether, these results indicate that alkylamides could elicited dual effects, adding new evidences and mechanisms for these opposite actions in different doses. Although further research is needed, we confirmed that alkylamides displays local analgesic and/or anesthetic effects.
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http://dx.doi.org/10.1016/j.fitote.2018.11.001DOI Listing
November 2018

Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial.

J Headache Pain 2018 Nov 1;19(1):101. Epub 2018 Nov 1.

Neurophysiology and Pain Unit, University of Bari Aldo Moro, Bari, Italy.

Background: Non-invasive vagus nerve stimulation (nVNS) has been shown to be practical, safe, and well tolerated for treating primary headache disorders. The recent multicenter, randomized, double-blind, sham-controlled PRESTO trial provided Class I evidence that for patients with episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. We report additional pre-defined secondary and other end points from PRESTO that demonstrate the consistency and durability of nVNS efficacy across a broad range of outcomes.

Methods: After a 4-week observation period, 248 patients with episodic migraine with/without aura were randomly assigned to acute treatment of migraine attacks with nVNS (n = 122) or a sham device (n = 126) during a double-blind period lasting 4 weeks (or until the patient had treated 5 attacks). All patients received nVNS therapy during the subsequent 4-week/5-attack open-label period.

Results: The intent-to-treat population consisted of 243 patients. The nVNS group (n = 120) had a significantly greater percentage of attacks treated during the double-blind period that were pain-free at 60 (P = 0.005) and 120 min (P = 0.026) than the sham group (n = 123) did. Similar results were seen for attacks with pain relief at 60 (P = 0.025) and 120 min (P = 0.018). For the first attack and all attacks, the nVNS group had significantly greater decreases (vs sham) in pain score from baseline to 60 min (P = 0.029); the decrease was also significantly greater for nVNS at 120 min for the first attack (P = 0.011). Results during the open-label period were consistent with those of the nVNS group during the double-blind period. The incidence of adverse events (AEs) and adverse device effects was low across all study periods, and no serious AEs occurred.

Conclusions: These results further demonstrate that nVNS is an effective and reliable acute treatment for multiple migraine attacks, which can be used safely while preserving the patient's option to use traditional acute medications as rescue therapy, possibly decreasing the risk of medication overuse. Together with its practicality and optimal tolerability profile, these findings suggest nVNS has value as a front-line option for acute treatment of migraine.

Trial Registration: ClinicalTrials.gov identifier: NCT02686034 .
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http://dx.doi.org/10.1186/s10194-018-0929-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755599PMC
November 2018