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1.
Muscle Nerve ; 60(4): 367-375, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31107560

RESUMO

INTRODUCTION: Topical application of lidocaine-and-prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique. METHODS: Small sensory fibers were selectively blocked by 120-minute topical application of LP and confirmed by quantitative sensory testing. Excitability changes of small (activated by a specially designed pin electrode) and large (patch electrode) nerve fibers were assessed as the strength-duration relation and threshold electrotonus. RESULTS: The excitability assessed by the strength-duration relation and threshold electrotonus was significantly modulated for the small afferents (P < 0.05, Wilcoxon's test) but not the large afferents. DISCUSSION: This novel PTT technique was able to assess inhibition of membrane properties of small cutaneous fibers, suggesting the usefulness of the technique as a diagnostic method for assessing impairment of small fibers, as seen in many types of polyneuropathies.


Assuntos
Anestésicos Locais/farmacologia , Combinação Lidocaína e Prilocaína/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Neuropatia de Pequenas Fibras/diagnóstico , Administração Cutânea , Adulto , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Eletrodiagnóstico , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Limiar Sensorial/fisiologia , Adulto Jovem
2.
Neuroscience ; 410: 55-58, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047975

RESUMO

Acute cutaneous exposure to allergen often leads to itch, but seldom pain. The effect of mast cell activation on cutaneous C-fibers was studied using innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Allergen (ovalbumin) injection into the isolated skin of actively sensitized mice strongly stimulated chloroquine (CQ)-sensitive C-fibers (also referred to as "itch" nerves); on the other hand, CQ-insensitive C-fibers were activated only modestly, if at all. The histamine H1 receptor antagonist pyrilamine abolished itch C-fibers response to histamine, but failed to significantly reduce the response to ovalbumin. Ovalbumin also strongly activated itch C-fibers in skin isolated from Mrgpr-cluster Δ-/- mice. When pyrilamine was studied in the Mrgpr-cluster Δ-/- mice thereby eliminating the influence of both histamine H1 and Mrgpr receptors (MrgprA3 and C11 are selectively expressed by itch nerves), the ovalbumin response was very nearly eliminated. The data indicate that the acute activation of itch C-fibers in mouse skin is largely secondary to the combined effect of activation of histamine H1 and Mrpgr receptors.


Assuntos
Alérgenos/toxicidade , Histamina/metabolismo , Terminações Nervosas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Prurido/metabolismo , Pele/metabolismo , Animais , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terminações Nervosas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Prurido/induzido quimicamente , Pele/efeitos dos fármacos , Pele/inervação
3.
Pulm Pharmacol Ther ; 56: 15-19, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30872160

RESUMO

Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because stimulation of vagal C-fibers leads to strong urge to cough sensations, and because C-fiber terminals can be strongly activated by mediators associated with airway inflammation. The most direct manner in which a given mediator can activate a C-fiber terminal is through interacting with its receptor expressed in the terminal membrane. The agonist-receptor interaction then must lead to the opening (or potentially closing) of ion channels that lead to a membrane depolarization. This depolarization is referred to as a generator potential. If, and only if, the generator potential reaches the voltage necessary to activate voltage-gated sodium channels, action potentials are initiated and conducted to the central terminals within the CNS. Therefore, there are three target areas to block the inflammatory mediator induced activation of C-fiber terminals. First, at the level of the mediator-receptor interaction, secondly at the level of the generator potential, and third at the level of the voltage-gated sodium channels. Here we provide a brief overview of each of these therapeutic strategies.


Assuntos
Antitussígenos/farmacologia , Tosse/tratamento farmacológico , Fibras Nervosas Amielínicas/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Tosse/fisiopatologia , Humanos , Fibras Nervosas Amielínicas/metabolismo , Nervo Vago/metabolismo , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismo
4.
Eur J Pharmacol ; 849: 154-159, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30716310

RESUMO

Previously, we showed that the synthetic nitroderivative trans-4-methyl-ß-nitrostyrene (T4MeN) induced vasorelaxant effects in rat isolated aortic rings. Here, we investigated the mechanisms underlying the cardiovascular effects of T4MeN in normotensive rats. In pentobarbital-anesthetized rats, intravenous (i.v.) injection of T4MeN (0.03-0.5 mg/kg) induced a rapid (onset time of 1-2 s) and dose-dependent bradycardia and hypotension. These cardiovascular responses to T4MeN were abolished by bilateral cervical vagotomy or selective blockade of neural conduction of vagal C-fiber afferents by perineural treatment of both cervical vagus nerves with capsaicin. Hypotension and bradycardia were also recorded when T4MeN was directly injected in the right, but not into the left ventricle. Furthermore, they were significantly reduced by i.v. pretreatment with capsazepine but remained unaltered by ondansetron or suramin. In conscious rats, the dose-dependent hypotension and bradycardia evoked by T4MeN were abolished by i.v. methylatropine pretreatment. In conclusion, bradycardiac and depressor responses induced by T4MeN has a vago-vagal reflex origin resulting from the vagal pulmonary afferents stimulation. The transduction mechanism seems to involve the activation of vanilloid TRPV1, but not purinergic (P2X) or 5-HT3 receptors located on vagal pulmonary sensory nerves.


Assuntos
Bradicardia/induzido quimicamente , Pulmão/inervação , Fibras Nervosas Amielínicas/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Estirenos/farmacologia , Canais de Cátion TRPV/metabolismo , Nervo Vago/efeitos dos fármacos , Animais , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Masculino , Fibras Nervosas Amielínicas/metabolismo , Fibras Nervosas Amielínicas/fisiologia , Ratos , Ratos Wistar
5.
J Neurophysiol ; 121(5): 1591-1608, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30625007

RESUMO

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT1D receptor labeling was not found on large proprioceptive afferents or α-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways. NEW & NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT1D receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT1D receptor plasticity.


Assuntos
Fibras Nervosas Amielínicas/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Reflexo de Estiramento , Traumatismos da Medula Espinal/metabolismo , Animais , Feminino , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
6.
Neurogastroenterol Motil ; 31(4): e13543, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30663188

RESUMO

INTRODUCTION: Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. METHOD: We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. KEY RESULTS: Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. CONCLUSION AND INFERENCES: Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Esôfago/inervação , Lidocaína/análogos & derivados , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Acrilamidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Capsaicina/farmacologia , Esôfago/efeitos dos fármacos , Cobaias , Ácido Clorídrico/farmacologia , Lidocaína/farmacologia , Técnicas de Patch-Clamp , Canais de Cátion TRPV/antagonistas & inibidores
7.
Sci Rep ; 8(1): 14967, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297735

RESUMO

High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.


Assuntos
Hipertensão/terapia , Nervo Mediano/fisiopatologia , Fibras Nervosas Amielínicas/fisiologia , Estimulação Elétrica Nervosa Transcutânea/instrumentação , Adulto , Pressão Sanguínea/efeitos dos fármacos , Monitores de Pressão Arterial , Capsaicina/farmacologia , Eletrodos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Nervo Mediano/efeitos dos fármacos , Bloqueio Nervoso , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nervo Ulnar/efeitos dos fármacos , Nervo Ulnar/fisiopatologia , Punho
8.
Neurochem Res ; 43(8): 1660-1670, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29959648

RESUMO

It is well known that remifentanil, a widely used intravenous anesthesia drug, can paradoxically induce hyperalgesia. The underlying mechanisms are still not clear despite the wide investigations. The present study demonstrated that withdrawal from spinal application of remifentanil could dose-dependently induce long term potentiation (LTP) of C-fiber evoked field potentials. Remifentanil withdrawal could activate Src family kinases (SFKs) in microglia, and upregulate the expression of tumor necrosis factor alpha (TNFα) in spinal dorsal horn. Furthermore, pretreatment with either microglia inhibitor Minocycline, SFKs inhibitor PP2 or TNF αneutralization antibody could block remifentanil withdrawal induced spinal LTP, whereas supplement of recombinant rat TNFα to the spinal cord could reverse the inhibitory effect of Minocycline or PP2 on remifentanil withdrawal induced LTP. Our results suggested that TNFαrelease following SFKs activation in microglia is involved in the induction of LTP induced by remifentanil withdrawal.


Assuntos
Potenciação de Longa Duração/fisiologia , Microglia/enzimologia , Fibras Nervosas Amielínicas/fisiologia , Piperidinas/administração & dosagem , Células do Corno Posterior/enzimologia , Quinases da Família src/metabolismo , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Remifentanil , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia
9.
Am J Physiol Lung Cell Mol Physiol ; 315(4): L467-L475, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29847989

RESUMO

The electronic cigarette (e-cig) has been suggested as a safer alternative to tobacco cigarettes. However, the health effects of e-cigs on the airways have not been fully investigated. Nicotine, the primary chemical constituent of the e-cig aerosol, has been shown to stimulate vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit vigorous pulmonary defense reflexes, including airway constriction. In this study, we investigated the bronchomotor response to e-cig inhalation challenge in anesthetized guinea pigs and the mechanisms involved in regulating these responses. Our results showed that delivery of a single puff of e-cig aerosol into the lung triggered immediately a transient bronchoconstriction that sustained for >2 min. The increase in airway resistance was almost completely abolished by a pretreatment with either intravenous injection of atropine or inhalation of aerosolized lidocaine, suggesting that the bronchoconstriction was elicited by cholinergic reflex mechanism and stimulation of airway sensory nerves was probably involved. Indeed, electrophysiological recording further confirmed that inhalation of e-cig aerosol exerted a pronounced stimulatory effect on vagal bronchopulmonary C-fibers. These effects on airway resistance and bronchopulmonary C-fiber activity were absent when the e-cig aerosol containing zero nicotine was inhaled, indicating a critical role of nicotine. Furthermore, a pretreatment with nicotinic acetylcholine receptor antagonists by inhalation completely prevented the airway constriction evoked by e-cig aerosol inhalation. In conclusion, inhalation of a single puff of e-cig aerosol caused a transient bronchoconstriction that was mediated through cholinergic reflex and triggered by a stimulatory effect of nicotine on vagal bronchopulmonary C-fiber afferents.


Assuntos
Brônquios/patologia , Broncoconstrição/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Fibras Nervosas Amielínicas/patologia , Nicotina/administração & dosagem , Nervo Vago/patologia , Administração por Inalação , Aerossóis , Resistência das Vias Respiratórias , Animais , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Cobaias , Masculino , Fibras Nervosas Amielínicas/efeitos dos fármacos , Reflexo , Mecânica Respiratória , Nervo Vago/efeitos dos fármacos
10.
Mol Pharmacol ; 94(3): 1047-1056, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29941667

RESUMO

We evaluated the effect of voltage-gated sodium channel 1 (NaV1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds-itch C-fibers; second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds-nociceptors; and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold-C-LTMs. NaV1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the α-subunits of NaV1 in individual dorsal root ganglia neurons labeled from the same region of the skin. Our results show that virtually all nociceptors and itch C-fibers expressed the tetrodotoxin (TTX)-resistant channels NaV1.8 and NaV1.9. However, TTX applied selectively into the skin abolished the action potential firing in response to mechanical stimulation in 75% of the itch C-fibers, 100% of the nociceptors, and 100% of C-LTMs. NaV1.7 was the most commonly expressed TTX-sensitive NaV1 in all three C-fiber subtypes innervating the dorsal skin. Selectively blocking NaV1.7 abolished responses in about 40% of itch C-fibers, 65% of nociceptors, but only 20% of C-LTMs. Blocking NaV1.8 alone had no affect on the firing sensitivity of the C-fibers. However, in itch and nociceptive C-fibers where the activation was not inhibited with a NaV1.7 blocker, adding the NaV1.8 blocker silenced action potential discharge.


Assuntos
Potenciais de Ação/fisiologia , Mecanorreceptores/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Nociceptividade/fisiologia , Prurido/fisiopatologia , Canais de Sódio Disparados por Voltagem/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Masculino , Mecanorreceptores/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Estimulação Física/métodos , Pele/efeitos dos fármacos , Pele/inervação , Bloqueadores dos Canais de Sódio/farmacologia
11.
PLoS One ; 13(5): e0196791, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723257

RESUMO

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.


Assuntos
Analgésicos/isolamento & purificação , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Peptídeos/química , Bloqueadores dos Canais de Sódio/isolamento & purificação , Venenos de Aranha/química , Potenciais de Ação/efeitos dos fármacos , Substituição de Aminoácidos , Analgésicos/farmacologia , Animais , Capsaicina/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Gânglios Espinais/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Fibras Nervosas Amielínicas/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Técnicas de Patch-Clamp , Estimulação Física , Engenharia de Proteínas , Proteínas Recombinantes/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Tetrodotoxina/farmacologia
12.
Exp Brain Res ; 236(8): 2231-2244, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845449

RESUMO

Topically applied high-concentration capsaicin induces reversible dermo-epidermal denervation and depletion of capsaicin-sensitive nociceptors. This causes desensitization of distinct sensory modalities and is used to treat peripheral neuropathic pain and itch. For high-concentration capsaicin, the selectivity of loss of function and functional recovery rates of various afferent fibers subpopulations are unknown. This study used comprehensive quantitative sensory testing and vasomotor imaging to assess effectiveness, duration and sensory selectivity of high-concentration 8% capsaicin-ablation. Skin areas in 14 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 1 and 24 h and underwent comprehensive sensory and vasomotor testing at 1, 7 and 21 days postpatch removal. Tests consisted of thermal detection and pain thresholds, tactile and vibration detection thresholds, mechanical pain threshold and mechanical pain sensitivity as well as micro-vascular and itch reactivity to histamine provocations. The 24 h capsaicin drastically inhibited warmth detection (P < 0.001), heat pain (P < 0.001) as well as histamine-induced itch (P < 0.05) and neurogenic flare (P < 0.001), but had no impact on tactile sensitivity, cold detection and cold pain. A marginal decrease in mechanical pain sensitivity was observed (P < 0.05). Capsaicin for 1 h had limited and transient sensory effects only affecting warmth and heat sensations. Time-dependent functional recovery was almost complete 21 days after the 24 h capsaicin exposure, while recovery of neurogenic inflammatory responsiveness remained partial. The psychophysically assessed sensory deficiencies induced by the used 8% capsaicin-ablation correspond well with a predominant effect on TRPV1+-cutaneous fibers. The method is easy to apply, well tolerated, and utilizable for studies on, e.g., interactions between skin barrier, inflammation and capsaicin-sensitive afferents.


Assuntos
Capsaicina/farmacologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Prurido/tratamento farmacológico , Fármacos do Sistema Sensorial/farmacologia , Pele , Sensação Térmica/efeitos dos fármacos , Percepção do Tato/efeitos dos fármacos , Adolescente , Adulto , Capsaicina/administração & dosagem , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Masculino , Imagem de Perfusão , Prurido/induzido quimicamente , Fármacos do Sistema Sensorial/administração & dosagem , Pele/diagnóstico por imagem , Pele/efeitos dos fármacos , Pele/fisiopatologia , Fatores de Tempo , Adulto Jovem
13.
Neurogastroenterol Motil ; 30(9): e13359, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29673037

RESUMO

BACKGROUND: Activation and sensitization of visceral afferent nerves by inflammatory mediators play important roles in visceral nociception. Sphingosine-1-phosphate (S1P) is a lipid with intracellular and extracellular functions. Extracellularly, it can act as an autacoid via interactions with S1P receptors. The present study aims to determine the effect of S1P on esophageal vagal afferent nerve functions. METHODS: Extracellular single-unit recordings were performed in ex vivo guinea pig esophageal-vagal preparations. The action potentials (APs) evoked by mechanical distension and chemical perfusions applied to the vagal afferent nerve endings in the esophagus were recorded at their intact neuronal cell bodies in either nodose or jugular ganglia. The effects of S1P and its receptor subtype agonists on vagal afferents were recorded and compared. The expression of S1P receptors (S1PR1-3) in esophageal-labeled vagal nodose and jugular neurons was studied by single-cell RT-PCR. KEY RESULTS: Sphingosine-1-phosphate evoked AP discharges in almost all esophageal jugular but not nodose C-fibers without changing their responses to esophageal distension. Esophageal-labeled vagal nodose and jugular neurons highly expressed transcripts of S1PR1 and S1PR3. Agonists of S1PR1 and S1PR3 each partially mimicked S1P-induced effect in jugular C-fibers, suggesting that these receptors may contribute partially to S1P-induced activation effect on esophageal jugular C-fiber subtype. CONCLUSIONS & INFERENCES: These data, for the first time, demonstrated a selective activation effect of S1P on vagal afferent nerve subtype in the gastrointestinal tract. This may help to better understand its role in visceral inflammatory nociception.


Assuntos
Esôfago/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Esfingosina/análogos & derivados , Nervo Vago/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Esôfago/inervação , Cobaias , Masculino , Esfingosina/farmacologia
14.
Neurourol Urodyn ; 37(6): 1897-1903, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29508437

RESUMO

AIMS: We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. METHODS: BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." RESULTS: The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. CONCLUSION: The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Indóis/farmacologia , Mecanorreceptores/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação , Agentes Urológicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Animais , Implantes de Medicamento , Estimulação Elétrica , Indóis/administração & dosagem , Masculino , Contração Muscular/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Ratos , Ratos Wistar , Agentes Urológicos/administração & dosagem
15.
Neurourol Urodyn ; 37(6): 1889-1896, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29516546

RESUMO

AIMS: To investigate the role of nerve growth factor (NGF) in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS: Using 4-week SCI mice, single-filling cystometry and external urethral sphincter (EUS)-electromyography were performed under an awake condition. In some SCI mice, anti-NGF antibodies (10 µg/kg/h) were administered for 1 or 2 weeks before the urodynamic study. NGF levels in the bladder and L6/S1 spinal cord were assayed by ELISA. The transcript levels of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured by RT-PCR. RESULTS: In SCI mice, the area under the curve of non-voiding contractions (NVCs) during the storage phase was significantly decreased in both 1- and 2-week anti-NGF antibody-treated SCI groups. However, EUS-electromyogram parameters during voiding were not altered by the treatment. Bladder mucosal and spinal NGF levels were decreased after 2 weeks of anti-NGF antibody treatment. TRPA1 and TRPV1 transcripts in L6/S1 DRG were significantly decreased after 1- or 2-week anti-NGF treatment. CONCLUSIONS: In SCI mice, NGF is involved in the emergence of NVCs in association with increased expression of TRP receptors that are predominantly found in C-fiber afferent pathways. Thus, NGF targeting treatments could be effective for treating storage problems such as detrusor overactivity after SCI.


Assuntos
Fator de Crescimento Neural/antagonistas & inibidores , Traumatismos da Medula Espinal/complicações , Doenças Uretrais/tratamento farmacológico , Doenças da Bexiga Urinária/tratamento farmacológico , Animais , Anticorpos Bloqueadores/uso terapêutico , Eletromiografia , Feminino , Gânglios Espinais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/metabolismo , Fator de Crescimento Neural/metabolismo , Receptores Purinérgicos P2X/metabolismo , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Uretra/metabolismo , Uretra/fisiopatologia , Doenças Uretrais/etiologia , Doenças Uretrais/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/etiologia , Doenças da Bexiga Urinária/fisiopatologia
16.
J Neurophysiol ; 119(5): 1993-2000, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29465329

RESUMO

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1-15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4-5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.


Assuntos
Transporte Axonal/fisiologia , Hiperalgesia/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Neuralgia/fisiopatologia , Neurite (Inflamação)/fisiopatologia , Nervo Isquiático/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Transporte Axonal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Fatores de Tempo , Moduladores de Tubulina/farmacologia , Vimblastina/farmacologia
17.
Neurourol Urodyn ; 37(5): 1633-1640, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29464762

RESUMO

AIMS: Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR-2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single-unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats. METHODS: Female Sprague-Dawley rats were used. Effects of cumulative intravenous (i.v.) administrations of KPR-2579 (0.03-1 mg/kg) on deep body temperature were investigated (N = 18). In separate animals, effects of bolus administration of KPR-2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by intravesical instillation of 0.1% AA were investigated using cystometry (N = 57) in a conscious free-moving condition or urethane-anesthetized condition, and SAA measurements (N = 41) were performed in a urethane-anesthetized condition. RESULTS: KPR-2579 at any doses tested did not affect body temperature. In cystometry measurements, a high dose (0.3 mg/kg) of KPR-2579 counteracted the shortened intercontraction interval provoked by AA instillation. In SAA measurements, 48 single afferent fibers (n = 24 in each fiber) were isolated. AA instillations significantly increased the SAAs of C fibers, but not of Aδ fibers, in the presence of KPR-2579's vehicle and a low dose (0.03 mg/kg) of KPR-2579. Pretreatment with a high dose (0.3 mg/kg) of KPR-2579 significantly inhibited the AA-induced activation of C-fiber SAAs. CONCLUSION: The present results suggest that TRPM8 channels play a role in the AA-induced pathological activation of mechanosensitive bladder C fibers in rats. KRP-2579 may be a promising drug for hypersensitive bladder disorders.


Assuntos
Fibras Nervosas Amielínicas/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária Hiperativa/tratamento farmacológico , Ácido Acético , Animais , Feminino , Fibras Nervosas Amielínicas/fisiologia , Neurônios Aferentes/fisiologia , Ratos , Ratos Sprague-Dawley , Bexiga Urinária Hiperativa/induzido quimicamente
18.
Anesth Analg ; 127(1): 263-266, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28991117

RESUMO

We investigated the effect of isoflurane on 2 main types of thermal nociceptors: A-δ and C-fibers. Surprisingly, 1% inhaled isoflurane led to a hyperalgesic response to C-fiber thermal stimulation, whereas responses to A-δ thermal stimulation were blunted. We explored the hypothesis that differences in withdrawal behavior are mediated by differential expression of isoflurane-sensitive proteins between these types of thermal nociceptors. Multiple transcriptomic databases of peripheral neurons were integrated to reveal that isoflurane-susceptible proteins Htr3a, Kcna2, and Scn8a were enriched in thermosensitive A-δ neurons. This exploratory analysis highlights the differing role that volatile anesthetics might have on nociceptors in the peripheral nervous system.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Perfilação da Expressão Gênica/métodos , Isoflurano/administração & dosagem , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Nociceptores/efeitos dos fármacos , Administração por Inalação , Anestésicos Inalatórios/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Isoflurano/toxicidade , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.2/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Nociceptores/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo
19.
Eur J Pain ; 22(3): 511-526, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29082571

RESUMO

BACKGROUND: Vasopressin (AVP) seems to play a role as an antinociceptive neurohormone, but little is known about the peripheral site of action of its antinociceptive effects. Moreover, AVP can produce motor impairment that could be confused with behavioural antinociception. Finally, it is not clear which receptor is involved in the peripheral antinociceptive AVP effects. METHODS: In anaesthetized rats with end-tidal CO2 monitoring, extracellular unitary recordings were performed, measuring the evoked activity mediated by Aß-, Aδ-, C-fibres and post-discharge. Behavioural nociception and motor impairment were evaluated under subcutaneous AVP (0.1-10 µg) using formalin and rotarod tests. Selective antagonists to vasopressin (V1A R) or oxytocin receptors (OTR) were used. Additionally, vasopressin and oxytocin receptors were explored immunohistochemically in skin tissues. RESULTS: Subcutaneous AVP (1 and 10 µg/paw) induced antinociception and a transitory reduction of the end-tidal CO2 . The neuronal activity associated with Aδ- and C-fibre activation was diminished, but no effect was observed on Aß-fibres. AVP also reduced paw flinches in the formalin test and a transitory locomotor impairment was also found. The AVP-induced antinociception was blocked by the selective antagonist to V1A R (SR49059) or OTR (L368,899). Immunohistochemical evidence of skin VP and OT receptors is given. CONCLUSIONS: Subcutaneous AVP produces antinociception and behavioural analgesia. Both V1a and OTR participate in those effects. Our findings suggest that antinociception could be produced in a local manner using a novel vasopressin receptor located in cutaneous sensorial fibres. Additionally, subcutaneous AVP also produces important systemic effects such as respiratory and locomotor impairment. SIGNIFICANCE: Our findings support that AVP produces peripheral antinociception and behavioural analgesia in a local manner; nevertheless, systemic effects are also presented. Additionally, this is the first detailed electrophysiological analysis of AVP antinociceptive action after subcutaneous administration. The results are reasonably explained by the demonstration of V1A R and OTR in cutaneous fibres.


Assuntos
Potenciais Evocados/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Receptores de Ocitocina/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Vasopressinas/farmacologia , Analgésicos/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Indóis/farmacologia , Injeções Subcutâneas , Locomoção/efeitos dos fármacos , Masculino , Medição da Dor , Piperazinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores de Ocitocina/antagonistas & inibidores
20.
Am J Physiol Regul Integr Comp Physiol ; 314(3): R489-R498, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29187382

RESUMO

We have addressed the hypothesis that the opposing effects of bronchopulmonary C-fiber activation on cough are attributable to the activation of C-fiber subtypes. Coughing was evoked in anesthetized guinea pigs by citric acid (0.001-2 M) applied topically in 100-µl aliquots to the tracheal mucosa. In control preparations, citric acid evoked 10 ± 1 coughs cumulatively. Selective activation of the pulmonary C fibers arising from the nodose ganglia with either aerosols or continuous intravenous infusion of adenosine or the 5-HT3 receptor-selective agonist 2-methyl-5-HT nearly abolished coughing evoked subsequently by topical citric acid challenge. Delivering adenosine or 2-methyl-5-HT directly to the tracheal mucosa (where few if any nodose C fibers terminate) was without effect on citric acid-evoked cough. These actions of pulmonary administration of adenosine and 2-methyl-5-HT were accompanied by an increase in respiratory rate, but it is unlikely that the change in respiratory pattern caused the decrease in coughing, as the rapidly adapting receptor stimulant histamine also produced a marked tachypnea but was without effect on cough. In awake guinea pigs, adenosine failed to evoke coughing but reduced coughing induced by the nonselective C-fiber stimulant capsaicin. We conclude that bronchopulmonary C-fiber subtypes in guinea pigs have opposing effects on cough, with airway C fibers arising from the jugular ganglia initiating and/or sensitizing the cough reflex and the intrapulmonary C fibers arising from the nodose ganglia actively inhibiting cough upon activation.


Assuntos
Tosse/fisiopatologia , Fibras Nervosas Amielínicas/classificação , Gânglio Nodoso/fisiopatologia , Traqueia/inervação , Potenciais de Ação , Adenosina/administração & dosagem , Animais , Bradicinina/administração & dosagem , Ácido Cítrico , Tosse/induzido quimicamente , Tosse/prevenção & controle , Modelos Animais de Doenças , Cobaias , Histamina/administração & dosagem , Masculino , Fibras Nervosas Amielínicas/efeitos dos fármacos , Gânglio Nodoso/efeitos dos fármacos , Agonistas do Receptor Purinérgico P1/administração & dosagem , Reflexo , Taxa Respiratória , Serotonina/administração & dosagem , Serotonina/análogos & derivados , Agonistas do Receptor 5-HT3 de Serotonina/administração & dosagem
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