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Inflammatory Responses Acquired Following Environmental Exposures Are Involved in Pathogenesis of Musculoskeletal Pain
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Ritchie C. Shoemaker, James C. Ryan
At one time substance P was called capsaicin; its receptor TRPV1, is a nociceptive-specific ion channel [94]. This ion channel is activated by thermal injury and acidification as well. Other TRP ion channels are TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1.Toxins [95] known to induce TRPV1 activation include scorpion venom, botulinum neurotoxin, spider toxin (NB: species not identified), ciguatoxin and brevetoxins. Vanillotoxins from a tarantula activate TRPV1 “via interaction with a region of TRPV1 that is homologous to voltage dependent ion channels.”
Central Projections of Baroreceptor and Chemoreceptor Afferent Fibers in the Rat
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
John Ciriello, Susan L. Hochstenbach, Stefanie Roder
Microinjections of the l-Glu antagonist glutamate diethyl ester (GDEE) have been shown to block the response to NTS injections of l-Glu at the same site and the reflex bradycardia elicited by the increase in arterial pressure as a result of the intravenous injections of phenylephrine.62 Furthermore, it has been shown that unilateral injections of GDEE into NTS markedly inhibit the depressor and bradycardic responses to stimulation of the ipsilateral ADN.63 Similarly, injections of the excitatory amino acids antagonist kynurenic acid (KYN) into NTS have been shown to block the cardiovascular effects of l-Glu, NMDA, AMPA, quis, and KA, as well as the cardiovascular responses to ipsilateral ADN stimulation.57,58,60,63d,l-2-amino-5-phospho-novalerate (APV), an NMDA antagonist, injected into NTS also blocked the response to NMDA, but greater concentrations of the antagonist were required to block the cardiovascular effects of either central injections of l-Glu or reflex activation of arterial baroreceptors.57 APV was also shown to be unable to alter the responses to quis or KA. However, when APV was injected unilaterally into medial NTS, a decrease in the depressor and bradycardia responses to ADN stimulation was observed.52 Kubo and Kihara63 also found that the NMDA antagonist MK-801 slightly inhibited the baroreflex responses elicited during ADN stimulation when injected ipsilaterally into NTS. On the other hand, the l-Glu receptor antagonist Joro spider toxin did not alter the baroreflex responses.63
Sympathetic Neurotransmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The N-type Ca2+ channels are high-voltage-activated but are resistant to dihydropyridines, and exhibit smaller single channel conductance than do the L-type channels. They have been demonstrated exclusively in neuronal tissue. Patch-clamp studies have demonstrated that ω-conotoxin GVIA, a 27 amino acid peptide from the marine snail, Conus geographus, inhibits the L- and N-type calcium channels in dorsal root ganglia, sensory and sympathetic neurones but not in smooth or cardiac muscle cells (McCleskey et al. 1987). The responses of several tissues, such as the vas deferens (Brock et al. 1989), mesenteric arteries (Pruneau & Angus 1990) and atria (De Luca et al. 1990), to sympathetic nerve stimulation have been shown to be blocked by ω-conotoxin, without block of the smooth muscle response to exogenously added noradrenaline (Figure 2.3). The dihydropyridine L-type channel blockers inhibit vascular smooth muscle contraction (Godfraind et al. 1986), but require considerably higher concentrations to inhibit noradrenaline release from sympathetic nerves (Gothert et al. 1979). This, and the fact that ω-conotoxin does not inhibit the smooth muscle response, which is dependent upon Ca2+ influx through L-type channels, suggests that the release of noradrenaline is induced by the influx of Ca2+ through N-type channels. Blockade of the propagation of the action potential by ω-conotoxin was not involved in its inhibitory action. This contrasts with the action of tetrodotoxin (TTX) which also abolishes the response to sympathetic nerve stimulation but by selectively blocking membrane Na+ channels of nerves rather than smooth or cardiac muscle (Figure 2.3). The high voltage Ca2+channels of adrenal chromaffin cells are insensitive to both dihydropyridines and ω-conotoxin and are therefore neither L-v N- or T-channels. It is not certain yet whether the release of adrenaline from chromaffin cells is therefore due to influx of Ca2+ through the P-type channel and susceptible to blockade by the funnel web spider toxin, FTX.
Antinociceptive peptides from venomous arthropods
Published in Toxin Reviews, 2023
Jessica A. I. Muller, Lai Y. Chan, Monica C. Toffoli-Kadri, Marcia R. Mortari, David J. Craik, Johannes Koehbach
To date, µ-TRTX-Hl1a is the only antinociceptive peptide isolated from the spider H. lividum. This peptide was evaluated by Meng et al. (2016) and the authors showed that it selectively blocks Nav1.8 channels and also has an analgesic effect in four murine models of nociception (formalin, acetic acid, tail-flick and hot plate assays), acting on both neuropathic and inflammatory pain with better activity in the former (Meng et al.2016). This peptide has 39 residues and a molecular weight of 4354.9 Da. From its structural analysis, this peptide showed an ICK motif around eight cysteines that form four disulfide-bonds between Cys3–Cys17, Cys10–Cys21, Cys16–Cys38 and Cys28–Cys34. The predicted 3D structure shows the presence of two α-helices and two β-sheets appears to be similar to Aps III an insecticidal spider toxin with an atypical ICK pattern (Meng et al.2016). Aps III has the typical ICK motif formed by three disulfide bonds but an additional disulfide bond that is stabilizing a beta hairpin loop motif (Bende et al.2013).
Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis
Published in Platelets, 2021
Maggie L. Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M. Ward, James I. Hearn, Justin R. Hamilton, Anna Y. Bogdanova
Further experiments by Morrell et al. provided powerful evidence corroborating AMPAR and KAR contribution to platelet activation [18,19]. Mice given CNQX and UBP302 have longer bleeding times and are protected from arterial thrombosis in the FeCl3 mesenteric artery thrombosis model (including longer times to platelet adhesion, thrombus formation, and vessel occlusion). Similar antithrombotic effects were observed following FeCl3 induced damage in the GRIA1 and GRIK2 knockout mice [18,19]. The mechanism of AMPAR and KAR effects in platelets involves an increase in intracellular Na+ leading to membrane depolarization, consistent with their neuronal activities, but not Ca2+ influx. These properties were confirmed in platelets using fluorescent Na+-sensitive probe and electrophysiological recordings in isolated mouse megakaryocytes [18]. AMPAR and KAR currents were small but consistently recorded in the presence of cyclothiazide (an allosteric inhibitor of desensitization). Joro spider toxin that inhibits Ca2+-permeable AMPAR had no effect on platelet activation by AMPA, arguing against AMPAR-mediated Ca2+ influx in platelets [18]. Kainate was also shown to activate the p38 MAPK signaling that operates upstream of cyclooxygenase 1 (COX-1) in platelets. KAR signaling increases COX activity and production of thromboxane A2 (platelet agonist), suggesting another mechanism for platelet activation by KAR independent of platelet membrane depolarization [19].
Using Xenopus oocytes in neurological disease drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Steven L. Zeng, Leland C. Sudlow, Mikhail Y. Berezin
Overuse of the opioid drugs to treat pain recently turned into the centre of attention in many developed countries. Due to the high risk of addiction, the opioid epidemic in the U.S. has become a national emergency that requires an immediate solution in the form of non-addictive drugs with no other side effects [107]. In that regard, Xenopus oocytes are frequently used as models for expressing proteins related to chronic pain and the search for new drugs. Thus, the search for more selective compounds to treat chronic pain has led to the study of a synthetic peptide PnPP-19 that resemble the active part of the known Phoneutria nigriventer spider toxin [108]. In this study, a variety of opioid receptors (i.e. human µ opioid receptor (hMOR), human k opioid receptor (hKOR), and human d opioid receptor (hDOR)) as well as ion channels (i.e. GIRK1, GIRK2) expressed in Xenopus oocytes were tested for their peptide specificity.