Background: Voltage-gated calcium channels (VGCCs) play an important role in pain development and maintenance. As Cav2.2 and Cav3.2 channels have been identified as potential drug targets for ...analgesics, the participation of Cav2.3 (that gives rise to R-type calcium currents) in pain and analgesia remains incompletely understood.
Objective: Identify the participation of Cav2.3 in pain and analgesia.
Methods: To map research in this area as well as to identify any existing gaps in knowledge on the potential role of Cav2.3 in pain signalling, we conducted this scoping review. We searched PubMed and SCOPUS databases, and 40 articles were included in this study. Besides, we organized the studies into 5 types of categories within the broader context of the role of Cav2.3 in pain and analgesia.
Results: Some studies revealed the expression of Cav2.3 in pain pathways, especially in nociceptive neurons at the sensory ganglia. Other studies demonstrated that Cav2.3-mediated currents could be inhibited by analgesic/antinociceptive drugs either indirectly or directly. Some articles indicated that Cav2.3 modulates nociceptive transmission, especially at the pre-synaptic level at spinal sites. There are studies using different rodent pain models and approaches to reduce Cav2.3 activity or expression and mostly demonstrated a pro-nociceptive role of Cav2.3, despite some contradictory findings and deficiencies in the description of study design quality. There are three studies that reported the association of single-nucleotide polymorphisms in the Cav2.3 gene (CACNA1E) with postoperative pain and opioid consumption as well as with the prevalence of migraine in patients.
Conclusion: Cav2.3 is a target for some analgesic drugs and has a pro-nociceptive role in pain.
Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by ...TRPA1) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type (Trpa1(+/+)) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice (P < 0.05-P < 0.001). Both genetic deletion of Trpa1 (Trpa1(-/-)) and pharmacological blockade (HC-030031 and A-967079) abrogated pain-like behaviours (both P < 0.001), which were abated by the antioxidant, α-lipoic acid, and the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin (both P < 0.001). Nociception and hypersensitivity evoked by constriction of the infraorbital nerve was associated with intra- and perineural monocytic and macrophagic invasion and increased levels of oxidative stress by-products (hydrogen peroxide and 4-hydroxynonenal). Attenuation of monocyte/macrophage increase by systemic treatment with an antibody against the monocyte chemoattractant chemokine (C-C motif) ligand 2 (CCL2) or the macrophage-depleting agent, clodronate (both P < 0.05), was associated with reduced hydrogen peroxide and 4-hydroxynonenal perineural levels and pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, α-lipoic acid or the anti-CCL2 antibody (all P < 0.001). The present findings propose that, in the constriction of the infraorbital nerve model of trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by-products released from monocytes and macrophages clumping at the site of nerve injury.
Glyceryl trinitrate administration causes prolonged mechanical allodynia in rodents, which correlates temporally with delayed migraine attacks in patients. Marone et al. show that the allodynia is ...mediated by TRPA1 activation in cell bodies of trigeminal neurons and ensuing oxidative stress. This neuronal pathway may be of relevance to migraine-like headaches.
Abstract
Glyceryl trinitrate is administered as a provocative test for migraine pain. Glyceryl trinitrate causes prolonged mechanical allodynia in rodents, which temporally correlates with delayed glyceryl trinitrate-evoked migraine attacks in patients. However, the underlying mechanism of the allodynia evoked by glyceryl trinitrate is unknown. The proalgesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by trigeminal nociceptors, is sensitive to oxidative stress and is targeted by nitric oxide or its by-products. Herein, we explored the role of TRPA1 in glyceryl trinitrate-evoked allodynia. Systemic administration of glyceryl trinitrate elicited in the mouse periorbital area an early and transient vasodilatation and a delayed and prolonged mechanical allodynia. The systemic, intrathecal or local administration of selective enzyme inhibitors revealed that nitric oxide, liberated from the parent drug by aldehyde dehydrogenase 2 (ALDH2), initiates but does not maintain allodynia. The central and the final phases of allodynia were respectively associated with generation of reactive oxygen and carbonyl species within the trigeminal ganglion. Allodynia was absent in TRPA1-deficient mice and was reversed by TRPA1 antagonists. Knockdown of neuronal TRPA1 by intrathecally administered antisense oligonucleotide and selective deletion of TRPA1 from sensory neurons in Advillin-Cre; Trpa1fl/fl mice revealed that nitric oxide-dependent oxidative and carbonylic stress generation is due to TRPA1 stimulation, and resultant NADPH oxidase 1 (NOX1) and NOX2 activation in the soma of trigeminal ganglion neurons. Early periorbital vasodilatation evoked by glyceryl trinitrate was attenuated by ALDH2 inhibition but was unaffected by TRPA1 blockade. Antagonists of the calcitonin gene-related peptide receptor did not affect the vasodilatation but partially inhibited allodynia. Thus, although both periorbital allodynia and vasodilatation evoked by glyceryl trinitrate are initiated by nitric oxide, they are temporally and mechanistically distinct. While vasodilatation is due to a direct nitric oxide action in the vascular smooth muscle, allodynia is a neuronal phenomenon mediated by TRPA1 activation and ensuing oxidative stress. The autocrine pathway, sustained by TRPA1 and NOX1/2 within neuronal cell bodies of trigeminal ganglia, may sensitize meningeal nociceptors and second order trigeminal neurons to elicit periorbital allodynia, and could be of relevance for migraine-like headaches evoked by glyceryl trinitrate in humans.
It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. Here we show that TRPA1 is also expressed in Schwann cells. We ...found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Activation of Schwann cell TRPA1 evoked NADPH oxidase 1 (NOX1)-dependent H
O
release, and silencing or blocking Schwann cell NOX1 attenuated nerve injury-induced macrophage infiltration, oxidative stress and allodynia. Furthermore, the NOX2-dependent oxidative burst, produced by macrophages recruited to the perineural space activated the TRPA1-NOX1 pathway in Schwann cells, but not TRPA1 in nociceptors. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia.
Emerging MIMO Technologies for 6G Networks Dala Pegorara Souto, Victoria; Dester, Plínio Santini; Soares Pereira Facina, Michelle ...
Sensors,
02/2023, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The demand for wireless connectivity has grown exponentially over the last years. By 2030 there should be around 17 billion of mobile-connected devices, with monthly data traffic in the order of ...thousands of exabytes. Although the Fifth Generation (5G) communications systems present far more features than Fourth Generation (4G) systems, they will not be able to serve this growing demand and the requirements of innovative use cases. Therefore, Sixth Generation (6G) Networks are expected to support such massive connectivity and guarantee an increase in performance and quality of service for all users. To deal with such requirements, several technical issues need to be addressed, including novel multiple-antenna technologies. Then, this survey gives a concise review of the main emerging Multiple-Input Multiple-Output (MIMO) technologies for 6G Networks such as massive MIMO (mMIMO), extremely large MIMO (XL-MIMO), Intelligent Reflecting Surfaces (IRS), and Cell-Free mMIMO (CF-mMIMO). Moreover, we present a discussion on how some of the expected key performance indicators (KPIs) of some novel 6G Network use cases can be met with the development of each MIMO technology.
•TRPA1 mediates allodynia in a mouse model of complex regional pain syndrome type I.•Allodynia is associated with macrophage accumulation in the injured tibial nerve.•Allodynia is dependent of TRPA1 ...agonists production by macrophage accumulation.•Schwann cell TRPA1 is essential to sustain neuroinflammation and allodynia.
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-CreERT;Trpa1fl/fl 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.
Acute gout attacks produce severe joint pain and inflammation associated with monosodium urate (MSU) crystals leading to oxidative stress production. The transient potential receptor ankyrin 1 ...(TRPA1) is expressed by a subpopulation of peptidergic nociceptors and, via its activation by endogenous reactive oxygen species, including hydrogen peroxide (H2O2), contributes to pain and neurogenic inflammation. The aim of this study was to investigate the role of TRPA1 in hyperalgesia and inflammation in a model of acute gout attack in rodents. Inflammatory parameters and mechanical hyperalgesia were measured in male Wistar rats and in wild-type (Trpa1+/+) or TRPA1-deficient (Trpa1−/−) male mice. Animals received intra-articular (ia, ankle) injection of MSU. The role of TRPA1 was assessed by receptor antagonism, gene deletion or expression, sensory fiber defunctionalization, and calcitonin gene-related peptide (CGRP) release. We found that nociceptor defunctionalization, TRPA1 antagonist treatment (via ia or oral administration), and Trpa1 gene ablation abated hyperalgesia and inflammatory responses (edema, H2O2 generation, interleukin-1β release, and neutrophil infiltration) induced by ia MSU injection. In addition, we showed that MSU evoked generation of H2O2 in synovial tissue, which stimulated TRPA1 producing CGRP release and plasma protein extravasation. The MSU-elicited responses were also reduced by the H2O2-detoxifying enzyme catalase and the reducing agent dithiothreitol. TRPA1 activation by MSU challenge-generated H2O2 mediates the entire inflammatory response in an acute gout attack rodent model, thus strengthening the role of the TRPA1 receptor and H2O2 production as potential targets for treatment of acute gout attacks.
Display omitted
•MSU-induced edema and hyperalgesia are largely mediated by TRPA1 receptor activation.•MSU ia injection increased TRPA1 expression in synovial tissue and CGRP release.•MSU increased H2O2 levels and NADPH-oxidase activity, but reduced CAT activity.•MSU-induced responses are mediated by H2O2 production and subsequent TRPA1 activation.•TRPA1 antagonism reduced MSU-induced neutrophil infiltration and IL-1β production.
There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by ...nociceptors, is activated by oxidizing substances to mediate pain‐like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16‐F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)‐deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1‐deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC‐030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after cancer cell inoculation. The antioxidant, α‐lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress‐independent pathway, contributes partially to heat hypersensitivity, oxidative stress‐dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.
What's new?
While cancer is a frequent cause of pain, mechanisms underlying the association are poorly understood. Moreover, therapeutic options for cancer pain are limited, and affected patients are undertreated. Here, using a mouse model of cancer pain, the authors identify transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by pain receptors, as a primary transducer of cancer pain. In animals, TRPA1 deletion attenuated sensitivity to mechanical and cold pain stimuli. Similar effects were produced upon TRPA1 blockade via pharmacological inhibition and TRPA1‐targeted antisense oligonucleotides. The findings warrant further investigation of TRPA1 antagonism as a means of treating cancer pain.
This study evaluated the anti-inflammatory properties of two sesquiterpenes isolated from
Cordia verbenacea's essential oil, α-humulene and (−)-
trans-caryophyllene. Our results revealed that oral ...treatment with both compounds displayed marked inhibitory effects in different inflammatory experimental models in mice and rats. α-humulene and (−)-
trans-caryophyllene were effective in reducing platelet activating factor-, bradykinin- and ovoalbumin-induced mouse paw oedema, while only α-humulene was able to diminish the oedema formation caused by histamine injection. Also, both compounds had important inhibitory effects on the mouse and rat carrageenan-induced paw oedema. Systemic treatment with α-humulene largely prevented both tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) generation in carrageenan-injected rats, whereas (−)-
trans-caryophyllene diminished only TNFα release. Furthermore, both compounds reduced the production of prostaglandin E
2 (PGE
2), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) expression, induced by the intraplantar injection of carrageenan in rats. The anti-inflammatory effects of α-humulene and (−)-
trans-caryophyllene were comparable to those observed in dexamethasone-treated animals, used as positive control drug. All these findings indicate that α-humulene and (−)-
trans-caryophyllene, derived from the essential oil of
C. verbenacea, might represent important tools for the management and/or treatment of inflammatory diseases.
Allosteric modulation of G-protein–coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions ...aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A ₄ is an endogenous allosteric enhancer of the CB ₁ cannabinoid receptor. Lipoxin A ₄ was detected in brain tissues, did not compete for the orthosteric binding site of the CB ₁ receptor (vs. ³H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A ₄ displayed a CB ₁ receptor-dependent protective effect against β-amyloid (1–40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB ₁ receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.
PDF
