International Journal of Molecular Sciences, Dec 4, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Prevalence of diabetes is increasing worldwide. 1 An estimate in 2013 illustrated 382 million peo... more Prevalence of diabetes is increasing worldwide. 1 An estimate in 2013 illustrated 382 million people globally had diabetes with the projection of 592 million people by the year 2035. In Pakistan nearly 6.7 million people has diabetes that is expected to rise to 12.8 million by the year 2035. Among total estimated population of diabetes, nearly 497,000 have type 1 diabetes. With an annual incidence rate of
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counterregulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified. The majority of these papers reported increased ACE2 levels in response to ACEI/ARB treatment. This result should be interpreted in the light of the dual role of ACE2 being a promoter of viral entry to cells and a protective factor against oxidative damage in the lungs.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon... more Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon kapott eredményeket humán preparátumokkal összevetve. Szenzoros és más eredetű nem-adrenerg, nem-cholinerg (NANC) transzmitterek azonosítása (funkcionális vizsgálatok és a transzmitterfelszabadulás mérése). Kóros zsigeri működések modellezése. (Egyes irányokban komplett, másokban tájékozódó kísérletek).
Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic ... more Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need.Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chr...
Background: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission ... more Background: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission in 5-26% and overall mortality can rise to 11% of the recognized cases, particularly affecting the elderly. There is a lack of evidence-based targeted pharmacological therapy for prevention and treatment alike. We aim to compare the effects of a World Health Organisation (WHO) recommendations’ based education and a personalised complex preventive lifestyle intervention package (based on the same WHO recommendation) on the outcomes of the COVID-19.Methods: PROACTIVE-19 is a pragmatic, randomized controlled clinical trial with adaptive “sample size re-estimation” design. Hungarian population over the age of 60 years without confirmed COVID-19 will be approached to participate in a telephone health assessment and lifestyle counselling voluntarily. Volunteers will be randomized into two groups: (A) general health education; (B) personalized health education. Participants will go through ques...
Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote antiinflamma... more Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote antiinflammatory effects throughout the body of anesthetized rats and guinea-pigs mediated by somatostatin. As somatostatin has also antinociceptive effects, the study aimed at investigating whether similar remote antinociceptive effects can be demonstrated in awake animals. In conscious rats, nociceptive nerve endings of the right hind paw decentralized by cutting the sciatic and saphenous nerves 18 h before were chemically stimulated, and drop of the noxious heat threshold (heat hyperalgesia) induced by prior (18 h before) plantar incision was measured on the contralateral, left hind paw using an increasing-temperature water bath. 18 h after nerve transection, mustard oil-evoked plasma extravasation was not significantly reduced in the right hind paw as tested by in vivo fluorescence imaging. Applying agonist of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptor (capsaicin or mustard oil, respectively) to the nerve-transected paw inhibited the plantar incision-induced drop of the noxious heat threshold on the contralateral paw. The onset of these remote antihyperalgesic effects was 10-20 min. A similar contralateral inhibitory effect of capsaicin or mustard oil treatment was observed on neuropathic mechanical hyperalgesia evoked by partial sciatic nerve injury 2 days before nerve transection and measured by a Randall-Selitto apparatus. The remote thermal antihyperalgesic effect was prevented by chronic (5 days) denervation or local capsaicin desensitization of the stimulated paw; reduced by intraperitoneally applied antagonist of somatostatin (cyclosomatostatin) or opioid receptors (naloxone). The response was mimicked by intraperitoneally applied somatostatin and associated with a 72+27 % increase in plasma somatostatin-like immunoreactivity that was absent after chronic (5 days) denervation.
Aims: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (... more Aims: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (AITC)-evoked nociceptive responses by comparing wild-type and genedeficient mice. Main methods: In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold.
A 2021. évi orvosi-élettani Nobel-díjjal David Julius amerikai és Ardem Patapoutian libanoni kuta... more A 2021. évi orvosi-élettani Nobel-díjjal David Julius amerikai és Ardem Patapoutian libanoni kutatók tudományos teljesítményét ismerték el a hőérzékelés és a tapintás molekuláris mechanizmusainak tisztátázásáért. David Julius és munkatársai azonosították a kapszaicin és a fájdalmas hőingerek (> 43 °C) érzékeléséért felelős kapszaicin-tranziens receptorpotenciál vanilloid 1 (TRPV1)-receptort, amely elsősorban kalciumot áteresztő, nem specifikus kationcsatornának bizonyult. Későbbi vizsgálatokban tisztázták, hogy a TRPV1-receptor alapvető szerepet játszik a hő-és gyulladásos fájdalom, valamint-elsősorban neuropeptidek felszabadítása révén-a beidegzés helyén értágulat, plazmafehérje-kiáramlás, simaizom, mirigy és egyéb szöveti reakciók közvetítésében. Ardem Patapoutian és munkatársai vizsgálatai vezettek a tapintásérzékelésben szerepet játszó mechanoszenzitív ioncsatornák, a Piezo1-és Piezo2-receptorok felfedezéséhez. Kimutatták, hogy ezek meghatározó szerepet játszanak a zsigeri szervek mechanoszenzitív működéseiben is. Jelen közleményünkben rávilágítunk azokra a hazai kutatók által tett alapvető felfedezésekre, amelyek hozzájárultak a kapszaicin/TRPV1-receptor azonosításához, valamint a kapszaicinérzékeny kemoszenzitív afferens idegek fájdalomérző és számos zsigeri működésben játszott komplex szabályozó szerepének megismeréséhez.
The bradykinin-induced sensitization of cutaneous nociceptors to heat was previously shown to be ... more The bradykinin-induced sensitization of cutaneous nociceptors to heat was previously shown to be abolished by cyclooxygenase blockade suggesting that endogenous prostaglandins exerted a heat-sensitizing action. The present study aimed at investigating the effects of exogenous prostaglandin E 2 (PGE 2) and I 2 (PGI 2) on noxious heat-evoked responses of rat cutaneous nociceptors. As neuropeptides including calcitonin generelated peptide (CGRP) can be released from the peptidergic subset of heat-sensitive nociceptors, both the spike-generating (afferent) and CGRPreleasing (efferent) responses to heat stimulation were assessed by recording action potentials from single cutaneous C-fibers and measuring immunoreactive CGRP (iCGRP) release from isolated skin flaps, respectively. A combination of PGE 2 and PGI 2 (100 μM for both) unlike 10 μM PGE 2 or PGI 2 increased the number of spikes discharged during a noxious heat stimulus whereas the heat threshold remained unchanged. In contrast, 100 μM PGE 2 plus PGI 2 failed to increase the iCGRP release induced by noxious heat (47°C) from the isolated rat skin. PGE 2 (100 μM), however, augmented the iCGRP-releasing effect of protons (pH 5.7). The adenylyl cyclase activator forskolin and the protein kinase C activator phorbol ester (PMA, 10 μM for both) facilitated heat-induced iCGRP release whereas increasing the intracellular Ca 2+ concentration by 10 μM ionomycin produced a desensitization of the response. In conclusion, PGE 2 plus PGI 2 can sensitize the afferent function of nociceptors in the rat skin, by increasing heat-induced spike discharge, but not the heat-induced efferent response i.e. iCGRP release. This discrepancy might reflect the differences between mechanisms of Na + channel-dependent spike generation and Ca 2+-dependent neuropeptide release.
Nociceptor Excitation by Sensitization: A Novel Hypothesis, Its Cellular and Molecular Background
Springer eBooks, 2000
Discovery of heat-activated ion channels and of the vanilloid receptors VR1 and VRL 1 in sensory ... more Discovery of heat-activated ion channels and of the vanilloid receptors VR1 and VRL 1 in sensory neurons of the spinal ganglion has shed new light on the transduction mechanisms by which inflammatory mediators and chemical irritants excite nociceptors and contribute to pain. Prostaglandin E2, histamine and, most potently, bradykinin and low pH as well as capsaicin and phorbol esters induce a prominent sensitization to heat of nociceptors including recruitment of previously unresponsive receptor terminals. Various membrane bound receptors and alternative second-messenger pathways, including PKC, cAMP and calcium influx, are involved in the transduction of the sensitizing effect. Putative heat-sensitive ion channels, including the vanilloid receptors, are the targets of the sensitizing action which is probably mediated by protein phosphorylation.
Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both ... more Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both excite and sensitize nociceptors to heat, mechanical, and chemical stimuli. Two types of bradykinin receptors (B1 and B2) have been identified of which the constitutive B2 receptors mediate most of the acute effects of bradykinin in uninflamed tissues while the B1 receptors are induced and become activated during inflammation. Both receptor subtypes utilize similar signaling pathways including activation of protein kinase C (PKC), elevation of intracellular Ca2+ concentration, and release of arachidonic acid. PKC activation is the major mechanism underlying the neuronal excitatory and heat-sensitizing actions of bradykinin while Ca2+ accumulation induces formation of nitric oxide within sensory neurons which is involved – together with receptor downregulation – in the development of tachyphylaxis of B2 receptor-mediated effects of bradykinin. Nitric oxide, however, may also contribute to the excitatory and sensitizing actions of bradykinin. Cyclooxygenase metabolites of arachidonic acid (prostanoids) may also be involved in both the excitatory and the sensitizing effects of bradykinin. Recently, a new signaling mechanism has been revealed for bradykinin which involves activation of the capsaicin TRPV1 receptor through PKC activation and formation of 12-lipoxygenase products of arachidonic acid. According to a novel hypothesis, the neuronal excitatory action of bradykinin is not a separate effect but in fact a heat response as a result of a massive heat sensitization with a threshold drop below the ambient temperature. Prostanoids can also sensitize nociceptors to heat, mechanical, and chemical stimuli predominantly via the cyclic adenosine 3′,5′-monophosphate–protein kinase A pathway that modulates various membrane channels including Ca2+-dependent or voltage-gated K+ channels, tetrodotoxin-resistant Na+ channels as well as ligand-gated or noxious heat-gated ion channels.
Bradykinin can excite C-polymodal nociceptors and sensitize them to heat and it can also enhance ... more Bradykinin can excite C-polymodal nociceptors and sensitize them to heat and it can also enhance prostaglandin synthesis, but it is unclear whether these effects are causally related. The role of cyclooxygenase products was investigated using two enantiomers of the cyclooxygenase inhibitor¯urbiprofen of which S(+)-is more potent than R(±)-¯urbiprofen. Single-unit activity was recorded from mechano-heat-sensitive, polymodal C-®bers in the isolated rat skin-saphenous nerve preparation. Bradykinin pretreatment (10 mM, 5 min) induced a 219 T 26% increase in the number of spikes evoked by noxious heat stimulation and a drop in the heat threshold by 5.2 T 0.6°C in a fully reproducible manner. S(+)-¯urbiprofen (1 mM) abolished the bradykinininduced heat sensitization but did not alter the unconditioned heat response itself. Under R(±)-¯urbiprofen (1 mM) bradykinin still induced a signi®cant heat sensitization which was reduced by 33 T 21% (P = 0.11) of its previous extent; this effect may be due to the limited purity of the enantiomer preparation or to a cyclooxygenase-independent action of¯urbiprofen. The heat sensitization suppressed by S(+)-¯urbiprofen could be signi®cantly restored (to 43 T 12%) by addition of PGE 2 plus PGI 2 (10 mM both) to bradykinin. Neither S(+)-nor R(±)-¯urbiprofen had an in¯uence on the magnitude of the excitatory effect of bradykinin. It is concluded that (i) cyclooxygenase products are the main mediators of nociceptor sensitization to heat following bradykinin treatment in the isolated rat skin; (ii) PGE 2 /I 2 are essential but perhaps not the only relevant cyclooxygenase products involved and (iii) neither S(+)-nor R(±)-¯urbiprofen inhibit the unconditioned noxious heat response and the excitatory bradykinin response of the polymodal C-nociceptors.
Peripheral mediators can contribute to the development and maintenance of inflammatory and neurop... more Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs. I. INTRODUCTION 1699 II. ROLE OF BRADYKININ IN PERIPHERAL... 1701 III. ROLE OF PROSTANOIDS IN... 1727 IV. ROLE OF LIPOXYGENASE PRODUCTS... 1744 V.
Effects of TRPV1 receptor antagonists on stimulated iCGRP release from isolated skin of rats and TRPV1 mutant mice
Pain, Jun 1, 2004
Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have ... more Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have recently been shown to inhibit the activation by noxious heat of the capsaicin receptor (TRPV1) expressed in non-neuronal host cells, and natively, in cultured dorsal root ganglion cells. Noxious heat has been shown to release immunoreactive calcitonin gene-related peptide (iCGRP) from the isolated rat skin. In this model, ruthenium red, I-RTX as well as capsazepine 10 microM caused no alteration in iCGRP release at 32 degrees C by themselves whereas capsazepine 100 microM doubled it reversibly. In wild-type mice 100 microM capsazepine also stimulated iCGRP release while it was without effect in TRPV1 knockout littermates. In the rat skin, both ruthenium red and capsazepine (10/100 microM) reduced and abolished, respectively, capsaicin-induced iCGRP release while I-RTX (1/10 microM) was ineffective. Only ruthenium red 100 microM showed an unspecific effect inhibiting iCGRP release induced by KCl. Ruthenium red and capsazepine (10/100 microM) caused no significant alteration of iCGRP release induced by heat stimulation at 47 degrees C. Employing 45 degrees C stimulation intensity, capsazepine and I-RTX (in the higher concentrations) showed a significant facilitatory effect on the heat response suggesting a partial agonistic action of the compounds. It is concluded that noxious heat-induced iCGRP release in the isolated rat skin occurs through a mechanism that is not inhibited by TRPV1 antagonism reflecting a different pharmacological profile of noxious heat transduction in terminals of sensory neurons compared to that in cultured cell bodies and TRPV1-transfected host cells.
NEUROPEPTIDES sity stimulation of A6 and C fibres induced a marked rise in CGRP-LM outflow (+ 193... more NEUROPEPTIDES sity stimulation of A6 and C fibres induced a marked rise in CGRP-LM outflow (+ 193 f 55%). Among the different noxious stimuli used, only noxious heat affected (f 135 * 34%) the release of CGRP-LM from the cervicotrigeminal area suggesting that participation of CGRPcontaining primary afferent fibres could be restricted to the transmission of some type of nociceptive information.
Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both ... more Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both excite and sensitize nociceptors to heat, mechanical, and chemical stimuli. Two types of bradykinin receptors (B1 and B2) have been identified of which the constitutive B2 receptors mediate most of the acute effects of bradykinin in uninflamed tissues while the B1 receptors are induced and become activated during inflammation. Both receptor subtypes utilize similar signaling pathways including activation of protein kinase C (PKC), elevation of intracellular Ca2+ concentration, and release of arachidonic acid. PKC activation is the major mechanism underlying the neuronal excitatory and heat-sensitizing actions of bradykinin while Ca2+ accumulation induces formation of nitric oxide within sensory neurons which is involved – together with receptor downregulation – in the development of tachyphylaxis of B2 receptor-mediated effects of bradykinin. Nitric oxide, however, may also contribute to the excitatory and sensitizing actions of bradykinin. Cyclooxygenase metabolites of arachidonic acid (prostanoids) may also be involved in both the excitatory and the sensitizing effects of bradykinin. Recently, a new signaling mechanism has been revealed for bradykinin which involves activation of the capsaicin TRPV1 receptor through PKC activation and formation of 12-lipoxygenase products of arachidonic acid. According to a novel hypothesis, the neuronal excitatory action of bradykinin is not a separate effect but in fact a heat response as a result of a massive heat sensitization with a threshold drop below the ambient temperature. Prostanoids can also sensitize nociceptors to heat, mechanical, and chemical stimuli predominantly via the cyclic adenosine 3′,5′-monophosphate–protein kinase A pathway that modulates various membrane channels including Ca2+-dependent or voltage-gated K+ channels, tetrodotoxin-resistant Na+ channels as well as ligand-gated or noxious heat-gated ion channels.
International Journal of Molecular Sciences, Dec 4, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Prevalence of diabetes is increasing worldwide. 1 An estimate in 2013 illustrated 382 million peo... more Prevalence of diabetes is increasing worldwide. 1 An estimate in 2013 illustrated 382 million people globally had diabetes with the projection of 592 million people by the year 2035. In Pakistan nearly 6.7 million people has diabetes that is expected to rise to 12.8 million by the year 2035. Among total estimated population of diabetes, nearly 497,000 have type 1 diabetes. With an annual incidence rate of
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counterregulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified. The majority of these papers reported increased ACE2 levels in response to ACEI/ARB treatment. This result should be interpreted in the light of the dual role of ACE2 being a promoter of viral entry to cells and a protective factor against oxidative damage in the lungs.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon... more Izolált szervi kísérletekben megismerni a zsigerek mozgásválaszainak mechanizmusait, az állatokon kapott eredményeket humán preparátumokkal összevetve. Szenzoros és más eredetű nem-adrenerg, nem-cholinerg (NANC) transzmitterek azonosítása (funkcionális vizsgálatok és a transzmitterfelszabadulás mérése). Kóros zsigeri működések modellezése. (Egyes irányokban komplett, másokban tájékozódó kísérletek).
Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic ... more Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need.Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chr...
Background: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission ... more Background: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission in 5-26% and overall mortality can rise to 11% of the recognized cases, particularly affecting the elderly. There is a lack of evidence-based targeted pharmacological therapy for prevention and treatment alike. We aim to compare the effects of a World Health Organisation (WHO) recommendations’ based education and a personalised complex preventive lifestyle intervention package (based on the same WHO recommendation) on the outcomes of the COVID-19.Methods: PROACTIVE-19 is a pragmatic, randomized controlled clinical trial with adaptive “sample size re-estimation” design. Hungarian population over the age of 60 years without confirmed COVID-19 will be approached to participate in a telephone health assessment and lifestyle counselling voluntarily. Volunteers will be randomized into two groups: (A) general health education; (B) personalized health education. Participants will go through ques...
Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote antiinflamma... more Stimulation of capsaicin-sensitive peripheral sensory nerve terminals induces remote antiinflammatory effects throughout the body of anesthetized rats and guinea-pigs mediated by somatostatin. As somatostatin has also antinociceptive effects, the study aimed at investigating whether similar remote antinociceptive effects can be demonstrated in awake animals. In conscious rats, nociceptive nerve endings of the right hind paw decentralized by cutting the sciatic and saphenous nerves 18 h before were chemically stimulated, and drop of the noxious heat threshold (heat hyperalgesia) induced by prior (18 h before) plantar incision was measured on the contralateral, left hind paw using an increasing-temperature water bath. 18 h after nerve transection, mustard oil-evoked plasma extravasation was not significantly reduced in the right hind paw as tested by in vivo fluorescence imaging. Applying agonist of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptor (capsaicin or mustard oil, respectively) to the nerve-transected paw inhibited the plantar incision-induced drop of the noxious heat threshold on the contralateral paw. The onset of these remote antihyperalgesic effects was 10-20 min. A similar contralateral inhibitory effect of capsaicin or mustard oil treatment was observed on neuropathic mechanical hyperalgesia evoked by partial sciatic nerve injury 2 days before nerve transection and measured by a Randall-Selitto apparatus. The remote thermal antihyperalgesic effect was prevented by chronic (5 days) denervation or local capsaicin desensitization of the stimulated paw; reduced by intraperitoneally applied antagonist of somatostatin (cyclosomatostatin) or opioid receptors (naloxone). The response was mimicked by intraperitoneally applied somatostatin and associated with a 72+27 % increase in plasma somatostatin-like immunoreactivity that was absent after chronic (5 days) denervation.
Aims: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (... more Aims: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (AITC)-evoked nociceptive responses by comparing wild-type and genedeficient mice. Main methods: In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold.
A 2021. évi orvosi-élettani Nobel-díjjal David Julius amerikai és Ardem Patapoutian libanoni kuta... more A 2021. évi orvosi-élettani Nobel-díjjal David Julius amerikai és Ardem Patapoutian libanoni kutatók tudományos teljesítményét ismerték el a hőérzékelés és a tapintás molekuláris mechanizmusainak tisztátázásáért. David Julius és munkatársai azonosították a kapszaicin és a fájdalmas hőingerek (> 43 °C) érzékeléséért felelős kapszaicin-tranziens receptorpotenciál vanilloid 1 (TRPV1)-receptort, amely elsősorban kalciumot áteresztő, nem specifikus kationcsatornának bizonyult. Későbbi vizsgálatokban tisztázták, hogy a TRPV1-receptor alapvető szerepet játszik a hő-és gyulladásos fájdalom, valamint-elsősorban neuropeptidek felszabadítása révén-a beidegzés helyén értágulat, plazmafehérje-kiáramlás, simaizom, mirigy és egyéb szöveti reakciók közvetítésében. Ardem Patapoutian és munkatársai vizsgálatai vezettek a tapintásérzékelésben szerepet játszó mechanoszenzitív ioncsatornák, a Piezo1-és Piezo2-receptorok felfedezéséhez. Kimutatták, hogy ezek meghatározó szerepet játszanak a zsigeri szervek mechanoszenzitív működéseiben is. Jelen közleményünkben rávilágítunk azokra a hazai kutatók által tett alapvető felfedezésekre, amelyek hozzájárultak a kapszaicin/TRPV1-receptor azonosításához, valamint a kapszaicinérzékeny kemoszenzitív afferens idegek fájdalomérző és számos zsigeri működésben játszott komplex szabályozó szerepének megismeréséhez.
The bradykinin-induced sensitization of cutaneous nociceptors to heat was previously shown to be ... more The bradykinin-induced sensitization of cutaneous nociceptors to heat was previously shown to be abolished by cyclooxygenase blockade suggesting that endogenous prostaglandins exerted a heat-sensitizing action. The present study aimed at investigating the effects of exogenous prostaglandin E 2 (PGE 2) and I 2 (PGI 2) on noxious heat-evoked responses of rat cutaneous nociceptors. As neuropeptides including calcitonin generelated peptide (CGRP) can be released from the peptidergic subset of heat-sensitive nociceptors, both the spike-generating (afferent) and CGRPreleasing (efferent) responses to heat stimulation were assessed by recording action potentials from single cutaneous C-fibers and measuring immunoreactive CGRP (iCGRP) release from isolated skin flaps, respectively. A combination of PGE 2 and PGI 2 (100 μM for both) unlike 10 μM PGE 2 or PGI 2 increased the number of spikes discharged during a noxious heat stimulus whereas the heat threshold remained unchanged. In contrast, 100 μM PGE 2 plus PGI 2 failed to increase the iCGRP release induced by noxious heat (47°C) from the isolated rat skin. PGE 2 (100 μM), however, augmented the iCGRP-releasing effect of protons (pH 5.7). The adenylyl cyclase activator forskolin and the protein kinase C activator phorbol ester (PMA, 10 μM for both) facilitated heat-induced iCGRP release whereas increasing the intracellular Ca 2+ concentration by 10 μM ionomycin produced a desensitization of the response. In conclusion, PGE 2 plus PGI 2 can sensitize the afferent function of nociceptors in the rat skin, by increasing heat-induced spike discharge, but not the heat-induced efferent response i.e. iCGRP release. This discrepancy might reflect the differences between mechanisms of Na + channel-dependent spike generation and Ca 2+-dependent neuropeptide release.
Nociceptor Excitation by Sensitization: A Novel Hypothesis, Its Cellular and Molecular Background
Springer eBooks, 2000
Discovery of heat-activated ion channels and of the vanilloid receptors VR1 and VRL 1 in sensory ... more Discovery of heat-activated ion channels and of the vanilloid receptors VR1 and VRL 1 in sensory neurons of the spinal ganglion has shed new light on the transduction mechanisms by which inflammatory mediators and chemical irritants excite nociceptors and contribute to pain. Prostaglandin E2, histamine and, most potently, bradykinin and low pH as well as capsaicin and phorbol esters induce a prominent sensitization to heat of nociceptors including recruitment of previously unresponsive receptor terminals. Various membrane bound receptors and alternative second-messenger pathways, including PKC, cAMP and calcium influx, are involved in the transduction of the sensitizing effect. Putative heat-sensitive ion channels, including the vanilloid receptors, are the targets of the sensitizing action which is probably mediated by protein phosphorylation.
Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both ... more Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both excite and sensitize nociceptors to heat, mechanical, and chemical stimuli. Two types of bradykinin receptors (B1 and B2) have been identified of which the constitutive B2 receptors mediate most of the acute effects of bradykinin in uninflamed tissues while the B1 receptors are induced and become activated during inflammation. Both receptor subtypes utilize similar signaling pathways including activation of protein kinase C (PKC), elevation of intracellular Ca2+ concentration, and release of arachidonic acid. PKC activation is the major mechanism underlying the neuronal excitatory and heat-sensitizing actions of bradykinin while Ca2+ accumulation induces formation of nitric oxide within sensory neurons which is involved – together with receptor downregulation – in the development of tachyphylaxis of B2 receptor-mediated effects of bradykinin. Nitric oxide, however, may also contribute to the excitatory and sensitizing actions of bradykinin. Cyclooxygenase metabolites of arachidonic acid (prostanoids) may also be involved in both the excitatory and the sensitizing effects of bradykinin. Recently, a new signaling mechanism has been revealed for bradykinin which involves activation of the capsaicin TRPV1 receptor through PKC activation and formation of 12-lipoxygenase products of arachidonic acid. According to a novel hypothesis, the neuronal excitatory action of bradykinin is not a separate effect but in fact a heat response as a result of a massive heat sensitization with a threshold drop below the ambient temperature. Prostanoids can also sensitize nociceptors to heat, mechanical, and chemical stimuli predominantly via the cyclic adenosine 3′,5′-monophosphate–protein kinase A pathway that modulates various membrane channels including Ca2+-dependent or voltage-gated K+ channels, tetrodotoxin-resistant Na+ channels as well as ligand-gated or noxious heat-gated ion channels.
Bradykinin can excite C-polymodal nociceptors and sensitize them to heat and it can also enhance ... more Bradykinin can excite C-polymodal nociceptors and sensitize them to heat and it can also enhance prostaglandin synthesis, but it is unclear whether these effects are causally related. The role of cyclooxygenase products was investigated using two enantiomers of the cyclooxygenase inhibitor¯urbiprofen of which S(+)-is more potent than R(±)-¯urbiprofen. Single-unit activity was recorded from mechano-heat-sensitive, polymodal C-®bers in the isolated rat skin-saphenous nerve preparation. Bradykinin pretreatment (10 mM, 5 min) induced a 219 T 26% increase in the number of spikes evoked by noxious heat stimulation and a drop in the heat threshold by 5.2 T 0.6°C in a fully reproducible manner. S(+)-¯urbiprofen (1 mM) abolished the bradykinininduced heat sensitization but did not alter the unconditioned heat response itself. Under R(±)-¯urbiprofen (1 mM) bradykinin still induced a signi®cant heat sensitization which was reduced by 33 T 21% (P = 0.11) of its previous extent; this effect may be due to the limited purity of the enantiomer preparation or to a cyclooxygenase-independent action of¯urbiprofen. The heat sensitization suppressed by S(+)-¯urbiprofen could be signi®cantly restored (to 43 T 12%) by addition of PGE 2 plus PGI 2 (10 mM both) to bradykinin. Neither S(+)-nor R(±)-¯urbiprofen had an in¯uence on the magnitude of the excitatory effect of bradykinin. It is concluded that (i) cyclooxygenase products are the main mediators of nociceptor sensitization to heat following bradykinin treatment in the isolated rat skin; (ii) PGE 2 /I 2 are essential but perhaps not the only relevant cyclooxygenase products involved and (iii) neither S(+)-nor R(±)-¯urbiprofen inhibit the unconditioned noxious heat response and the excitatory bradykinin response of the polymodal C-nociceptors.
Peripheral mediators can contribute to the development and maintenance of inflammatory and neurop... more Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs. I. INTRODUCTION 1699 II. ROLE OF BRADYKININ IN PERIPHERAL... 1701 III. ROLE OF PROSTANOIDS IN... 1727 IV. ROLE OF LIPOXYGENASE PRODUCTS... 1744 V.
Effects of TRPV1 receptor antagonists on stimulated iCGRP release from isolated skin of rats and TRPV1 mutant mice
Pain, Jun 1, 2004
Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have ... more Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have recently been shown to inhibit the activation by noxious heat of the capsaicin receptor (TRPV1) expressed in non-neuronal host cells, and natively, in cultured dorsal root ganglion cells. Noxious heat has been shown to release immunoreactive calcitonin gene-related peptide (iCGRP) from the isolated rat skin. In this model, ruthenium red, I-RTX as well as capsazepine 10 microM caused no alteration in iCGRP release at 32 degrees C by themselves whereas capsazepine 100 microM doubled it reversibly. In wild-type mice 100 microM capsazepine also stimulated iCGRP release while it was without effect in TRPV1 knockout littermates. In the rat skin, both ruthenium red and capsazepine (10/100 microM) reduced and abolished, respectively, capsaicin-induced iCGRP release while I-RTX (1/10 microM) was ineffective. Only ruthenium red 100 microM showed an unspecific effect inhibiting iCGRP release induced by KCl. Ruthenium red and capsazepine (10/100 microM) caused no significant alteration of iCGRP release induced by heat stimulation at 47 degrees C. Employing 45 degrees C stimulation intensity, capsazepine and I-RTX (in the higher concentrations) showed a significant facilitatory effect on the heat response suggesting a partial agonistic action of the compounds. It is concluded that noxious heat-induced iCGRP release in the isolated rat skin occurs through a mechanism that is not inhibited by TRPV1 antagonism reflecting a different pharmacological profile of noxious heat transduction in terminals of sensory neurons compared to that in cultured cell bodies and TRPV1-transfected host cells.
NEUROPEPTIDES sity stimulation of A6 and C fibres induced a marked rise in CGRP-LM outflow (+ 193... more NEUROPEPTIDES sity stimulation of A6 and C fibres induced a marked rise in CGRP-LM outflow (+ 193 f 55%). Among the different noxious stimuli used, only noxious heat affected (f 135 * 34%) the release of CGRP-LM from the cervicotrigeminal area suggesting that participation of CGRPcontaining primary afferent fibres could be restricted to the transmission of some type of nociceptive information.
Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both ... more Abstract Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both excite and sensitize nociceptors to heat, mechanical, and chemical stimuli. Two types of bradykinin receptors (B1 and B2) have been identified of which the constitutive B2 receptors mediate most of the acute effects of bradykinin in uninflamed tissues while the B1 receptors are induced and become activated during inflammation. Both receptor subtypes utilize similar signaling pathways including activation of protein kinase C (PKC), elevation of intracellular Ca2+ concentration, and release of arachidonic acid. PKC activation is the major mechanism underlying the neuronal excitatory and heat-sensitizing actions of bradykinin while Ca2+ accumulation induces formation of nitric oxide within sensory neurons which is involved – together with receptor downregulation – in the development of tachyphylaxis of B2 receptor-mediated effects of bradykinin. Nitric oxide, however, may also contribute to the excitatory and sensitizing actions of bradykinin. Cyclooxygenase metabolites of arachidonic acid (prostanoids) may also be involved in both the excitatory and the sensitizing effects of bradykinin. Recently, a new signaling mechanism has been revealed for bradykinin which involves activation of the capsaicin TRPV1 receptor through PKC activation and formation of 12-lipoxygenase products of arachidonic acid. According to a novel hypothesis, the neuronal excitatory action of bradykinin is not a separate effect but in fact a heat response as a result of a massive heat sensitization with a threshold drop below the ambient temperature. Prostanoids can also sensitize nociceptors to heat, mechanical, and chemical stimuli predominantly via the cyclic adenosine 3′,5′-monophosphate–protein kinase A pathway that modulates various membrane channels including Ca2+-dependent or voltage-gated K+ channels, tetrodotoxin-resistant Na+ channels as well as ligand-gated or noxious heat-gated ion channels.
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