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

Logu, Francesco De; Prá, Samira Dal-Toé De; Antoniazzi, Caren Tatiane de David; Kudsi, Sabrina Qader; Ferro, Paula Ronsani; Landini, Lorenzo; Rigo, Flávia Karine; Silveira, Gustavo de Bem; Silveira, Paulo César Lock; Oliveira, Sara Marchesan; Marini, Matilde; Mattei, Gianluca; Ferreira, Juliano; Geppetti, Pierangelo; Nassini, Romina; Trevisan, Gabriela

doi:10.1016/j.bbi.2020.04.037

Cited by 37 publications

(35 citation statements)

References 59 publications

(105 reference statements)

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Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

“…The temperature (cold) sensitivity of TRPA1 is subject to much debate and will not be discussed here, except to mention that Trpa1 –/– mice show attenuated cold allodynia evoked by anticancer drugs like oxaliplatin 83 , and by ischaemia and reperfusion injury of the rodent hindlimb, a murine model of complex regional pain syndrome type I (CRPS-I) 84 . Importantly, TRPA1 antagonists recapitulated the effects of genetic Trpa1 inactivation 84 , indicating a novel therapeutic strategy in CRPS-I patients. Trpa1 –/– mice also displayed reduced visceromotor responses to colorectal distension 85 , indicating a role for TRPA1 in mechanical pain; and Trpa1 –/– rats showed decreased pain behaviours in response to chemical agonists of TRPA1, but normal responses to other pain stimuli, including cold, and itching 86 .…”

Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

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Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

220

118

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Transient receptor potential (TRP) channels are multifunctional signalling molecules with many roles in sensory perception and cellular physiology. Therefore, it is not surprising that TRP channels have been implicated in numerous diseases, including hereditary disorders caused by defects in genes encoding TRP channels (TRP channelopathies). Most TRP channels are located at the cell surface, which makes them generally accessible drug targets. Early drug discovery efforts to target TRP channels focused on pain, but as our knowledge of TRP channels and their role in health and disease has grown, these efforts have expanded into new clinical indications, ranging from respiratory disorders through neurological and psychiatric diseases to diabetes and cancer. In this Review, we discuss recent findings in TRP channel structural biology that can affect both drug development and clinical indications. We also discuss the clinical promise of novel TRP channel modulators, aimed at both established and emerging targets. Last, we address the challenges that these compounds may face in clinical practice, including the need for carefully targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

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Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

220

118

View full text Add to dashboard Cite

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“…TRPA1 expressed in Schwann cells has been found to dynamically communicate with the ensheathed nerve fibers and with surrounding inflammatory cells (expanded peripheral nerve resident macrophages or invading hematogenic macrophages) via oxidative stress generation. The feed-forward mechanism that encompasses invading macrophages, oxidative stress, and Schwann cell TRPA1 was found to be essential to sustain mechanical allodynia in mouse models of neuropathic pain [ 56 ], and of complex regional pain syndrome type I [ 185 ]. In addition, Schwann cell TRPA1 has been reported to generate, in a macrophage-independent manner, oxidative stress, which sustains mechanical allodynia in a chronic murine model of alcoholic neuropathy [ 57 ].…”

Section: Expert Opinionmentioning

confidence: 99%

TRPA1 as a therapeutic target for nociceptive pain

Araújo

Nassini

Geppetti

et al. 2020

Expert Opinion on Therapeutic Targets

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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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“…The antinociceptive effects of these compounds was detected for 1–2 h in these MS models [ 43 , 44 ]. Apocynin and α-lipoic acid, when administered in mice in the doses used in this study, showed an antinociceptive effects for 1–2 h in other pain models [ 9 , 94 ]. Here, in a PMA model caused by PMS-EAE, we also observed the antiallodynic effect of apocynin and α-lipoic acid.…”

Section: Discussionmentioning

confidence: 99%

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

et al. 2021

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Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

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

Cited by 37 publications

References 59 publications

Advances in TRP channel drug discovery: from target validation to clinical studies

Advances in TRP channel drug discovery: from target validation to clinical studies

TRPA1 as a therapeutic target for nociceptive pain

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

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