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1.
J Med Invest ; 68(3.4): 383-385, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34759164

RESUMO

Background : Although an increase in sympathetic nerve activity is generally associated with a decrease in the photoplethysmography (PPG) amplitude, the present case study demonstrates that nociceptive stimuli, such as tracheal intubation, paradoxically induce an increase in PPG amplitude. To the best of our knowledge, this is the first study to capture an increase in the PPG amplitude in response to sympathetic nerve activation. Case presentation : A 73-year-old woman underwent open surgery. Following anesthesia induction, tracheal intubation was performed, which resulted in increased heart rate and raised blood pressure. While nociception usually decreases the PPG amplitude, the opposite was found. Conversely, the vascular stiffness K value, our research group's unique monitoring method to quantify the strength of sympathetic activity, increased reflecting increased peripheral vascular resistance. Conclusions : We report a paradoxical case of increased PPG amplitude following tracheal intubation. It is important to note that the PPG amplitude does not always decrease with nociceptive stimuli. J. Med. Invest. 68 : 383-385, August, 2021.


Assuntos
Nociceptividade , Fotopletismografia , Idoso , Anestesia Geral , Feminino , Humanos , Intubação Intratraqueal
2.
A A Pract ; 15(11): e01542, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34735416

RESUMO

Nociception is the detection of noxious stimulation by the nervous system. The PMD-200 monitor is a validated, emerging technology for intraoperative monitoring using the nociception level (NOL) index. We describe a pediatric case of an open resection of paraganglionic masses during which episodic increases in NOL index and blood pressure coincided with tumor manipulation, presumably due to a catecholamine surge. Since the patient was under stable and adequate analgesia, the increases in NOL index likely reflected the physiologic effects of tumor handling rather that the presence of a true noxious stimulus. Clinicians should consider this limitation when using this monitor.


Assuntos
Nociceptividade , Paraganglioma , Criança , Humanos , Monitorização Intraoperatória , Medição da Dor , Paraganglioma/cirurgia , Remifentanil
3.
Cells ; 10(10)2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34685772

RESUMO

Recent data show that activation of nociceptive (sensory) nerves turns on localized inflammation within the innervated area in a retrograde manner (antidromically), even in the absence of tissue injury or molecular markers of foreign invaders. This neuroinflammatory process is activated and sustained by the release of neuronal products, such as neuropeptides, with the subsequent amplification via recruitment of immunocompetent cells, including macrophages and lymphocytes. High mobility group box 1 protein (HMGB1) is a highly conserved, well characterized damage-associated molecular pattern molecule expressed by many cells, including nociceptors and is a marker of inflammatory diseases. In this review, we summarize recent evidence showing that neuronal HMGB1 is required for the development of neuroinflammation, as knock out limited to neurons or its neutralization via antibodies ameliorate injury in models of nerve injury and of arthritis. Further, the results of study show that HMGB1 is actively released during neuronal depolarization and thus plays a previously unrecognized key etiologic role in the initiation and amplification of neuroinflammation. Direct targeting of HMGB1 is a promising approach for novel anti-inflammatory therapy.


Assuntos
Proteína HMGB1/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Neurônios/metabolismo , Animais , Humanos , Modelos Biológicos , Nociceptividade , Receptor 4 Toll-Like/metabolismo
4.
Molecules ; 26(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684749

RESUMO

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.


Assuntos
Dor Crônica/tratamento farmacológico , Receptores de Angiotensina/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Humanos , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Manejo da Dor/métodos , Receptores de Angiotensina/metabolismo , Receptores Opioides/agonistas , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
5.
Life Sci ; 285: 120014, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34619167

RESUMO

AIMS: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated. MAIN METHODS: One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus - pulse oximeter. KEY FINDINGS: In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect. SIGNIFICANCE: These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an "opioid sparing" strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia.


Assuntos
Analgesia/métodos , Analgésicos Opioides/farmacologia , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Benzilaminas/administração & dosagem , Benzilaminas/farmacologia , Ciclamos/administração & dosagem , Ciclamos/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Masculino , Maraviroc/administração & dosagem , Maraviroc/farmacologia , Morfina/administração & dosagem , Morfina/efeitos adversos , Dor Nociceptiva/fisiopatologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Tiazóis/administração & dosagem , Tiazóis/farmacologia
6.
Neurologia (Engl Ed) ; 36(8): 584-588, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34654532

RESUMO

INTRODUCTION: Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful. METHODS: Eight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13cm. The animals' tails were immersed in the container with a starting temperature of 36°C. The water temperature was raised in 1°C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water. RESULTS: Six of the 8 mice began shaking their tails at the temperature of 51°C. All animals removed their tails from the water at the temperatures of 54°C, 55°C, and 56°C, taking a mean time of 8.54, 7.99, and 5.33seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). CONCLUSIONS: The response time was statistically similar for the temperatures of 54°C, 55°C, and 56°C; however, the data were less dispersed for the latter temperature.


Assuntos
Nociceptividade , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tempo de Reação , Temperatura
7.
Anesthesiology ; 135(5): 877-892, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610092

RESUMO

BACKGROUND: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. METHODS: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. RESULTS: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). CONCLUSIONS: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.


Assuntos
Anestesia Geral , Encéfalo/fisiologia , Hemodinâmica/fisiologia , Nociceptividade/fisiologia , Vigília/fisiologia , Adulto , Encéfalo/efeitos dos fármacos , Feminino , Humanos , Masculino , Espectroscopia de Luz Próxima ao Infravermelho , Adulto Jovem
8.
Nutrients ; 13(9)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34578829

RESUMO

Trehalose, a sugar from fungi, mimics starvation due to a block of glucose transport and induces Transcription Factor EB- mediated autophagy, likely supported by the upregulation of progranulin. The pro-autophagy effects help to remove pathological proteins and thereby prevent neurodegenerative diseases such as Alzheimer's disease. Enhancing autophagy also contributes to the resolution of neuropathic pain in mice. Therefore, we here assessed the effects of continuous trehalose administration via drinking water using the mouse Spared Nerve Injury model of neuropathic pain. Trehalose had no effect on drinking, feeding, voluntary wheel running, motor coordination, locomotion, and open field, elevated plus maze, and Barnes Maze behavior, showing that it was well tolerated. However, trehalose reduced nerve injury-evoked nociceptive mechanical and thermal hypersensitivity as compared to vehicle. Trehalose had no effect on calcium currents in primary somatosensory neurons, pointing to central mechanisms of the antinociceptive effects. In IntelliCages, trehalose-treated mice showed reduced activity, in particular, a low frequency of nosepokes, which was associated with a reduced proportion of correct trials and flat learning curves in place preference learning tasks. Mice failed to switch corner preferences and stuck to spontaneously preferred corners. The behavior in IntelliCages is suggestive of sedative effects as a "side effect" of a continuous protracted trehalose treatment, leading to impairment of learning flexibility. Hence, trehalose diet supplements might reduce chronic pain but likely at the expense of alertness.


Assuntos
Comportamento Animal/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Nervo Isquiático/lesões , Trealose/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Nervo Isquiático/efeitos dos fármacos
10.
BMJ ; 374: n1448, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34526307

RESUMO

OBJECTIVE: To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine. DESIGN: Three arm, parallel group, randomized, modified double blind, controlled trial. SETTING: Ambulatory, academic medical center in the United States over 16 weeks. PARTICIPANTS: 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine). INTERVENTIONS: Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)-increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)-increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)-maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of energy. All participants received foods accounting for two thirds of daily food energy and continued usual care. MAIN OUTCOME MEASURES: The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. RESULTS: In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (-1.6, -4.2 to 1.0, and -1.5, -4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (-1.7, -2.5 to -0.9, and -1.3, -2.1 to -0.5, respectively), moderate to severe headache hours per day (-0.8, -1.2 to -0.4, and -0.7, -1.1 to -0.3, respectively), and headache days per month (-4.0, -5.2 to -2.7, and -2.0, -3.3 to -0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, -3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2. CONCLUSIONS: The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT02012790.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-6/administração & dosagem , Transtornos de Enxaqueca/dietoterapia , Adulto , Ácidos Docosa-Hexaenoicos/sangue , Método Duplo-Cego , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nociceptividade , Autorrelato , Índice de Gravidade de Doença
11.
ACS Chem Neurosci ; 12(19): 3760-3771, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34553902

RESUMO

Despite major advances, not all patients achieve rheumatoid arthritis (RA) remission, thus highlighting a pressing need for new therapeutic treatments. Given this scenario, this study sought to evaluate Se-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl] 4-chlorobenzoselenolate (Se-DMC) potential on a complete Freund's adjuvant (CFA)-induced unilateral arthritis model. The effects of Se-DMC (5 mg/kg; oral dose) and meloxicam (5 mg/kg; oral dose), both administered to animals daily for 14 days, on paw edema, mechanical sensitivity, neurobehavioral deficits (anxiogenic- and depressive-like behaviors), Na+/K+-ATPase activity, oxidative stress, and inflammation were evaluated in male Swiss mice exposed to CFA (intraplantar injection of 0.1 mL; 10 mg/mL). Se-DMC reduced the paw withdrawal threshold and CFA-induced paw edema. Histopathological results revealed the antiedematogenic potential of the compound, which was evidenced by lower quantities of dilated lymphatic vessels compared with the CFA group. Se-DMC reduced mRNA relative expression levels of tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) in the hippocampus and paw of CFA mice. The CFA-induced anxiogenic- and depressive-like behaviors were reversed by Se-DMC to the control levels in the elevated plus-maze and tail suspension tests. Se-DMC reduced the paw reactive species levels and restored the superoxide dismutase (hippocampus and paw) and Na+/K+-ATPase (hippocampus) activities previously increased by CFA. Moreover, CFA administration inhibited serum creatinine kinase activity, albeit the Se-DMC effects did not appear to involve the modulation of this enzyme and were equal to or greater than meloxicam. Se-DMC attenuates CFA-induced inflammatory response, nociception, and neurobehavioral deficits in mice.


Assuntos
Artrite Reumatoide , Nociceptividade , Animais , Artrite Reumatoide/tratamento farmacológico , Adjuvante de Freund/toxicidade , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Transtornos do Humor
12.
Neuroscience ; 475: 117-126, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34530103

RESUMO

Oxytocin is a hypothalamic neuropeptide involved in the inhibition of nociception transmission at spinal dorsal horn (SDH) level (the first station where the incoming peripheral signals is modulated). Electrophysiological, behavioral, and pharmacological data strongly support the role of this neuropeptide and its receptor (the oxytocin receptor, OTR) as a key endogenous molecule with analgesic properties. Briefly, current data showed that oxytocin release from the hypothalamus induces OTR activation at the SDH, inducing selective inhibition of the nociceptive Aδ- and C-fibers (probably peptidergic) activity, but not the activity of proprioceptive fibers (i.e. Aß-fibers). The above inhibition could be a direct presynaptic mechanism, or a mechanism mediated by GABAergic interneurons. However, the exact anatomical localization of oxytocin and OTR remains unclear. In this context, the present study set out to analyze the role of OTRs, GABAergic cells and CGRP fibers in the SDH in rats by using electron microscopy. Ultrastructural analyses of the SDH tissue show that: (i) oxytocin and OTR are found in asymmetrical synapsis; (ii) OTR is found in GABAergic interneurons (near unmyelinated fibers), CGRPergic fibers and glial cells; (iii) whereas oxytocin is present in supraspinal descending projection fibers. These anatomical data strongly support the notion that oxytocin released at the SDH could presynaptically inhibit the nociceptive input from the peripheral primary afferent fibers. This inhibitory action could be direct or use a GABA interneuron. Furthermore, our findings that OTR is exhibited in glial tissue at the SDH requires further exploration in nociception assays.


Assuntos
Nociceptividade , Receptores de Ocitocina , Animais , Fibras Nervosas Amielínicas , Ocitocina , Células do Corno Posterior , Ratos , Corno Dorsal da Medula Espinal
13.
J Vet Med Sci ; 83(10): 1570-1581, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34470979

RESUMO

The activation of α2 adrenergic receptors contributes to analgesia not only in the central nervous system but also in the peripheral nervous system. We reported that noradrenaline inhibits the activity of transient receptor potential vanilloid 1 (TRPV1) evoked by capsaicin through α2 receptors in cultured rat dorsal root ganglion (DRG) neurons. However, it is unclear whether activation of TRPV1 expressed in peripheral nerve terminals is inhibited by α2 receptors and whether this phenomenon contributes to analgesia. Therefore, we examined effects of clonidine, an α2 receptor agonist, on several types of nociceptive behaviors, which may be caused by TRPV1 activity, and subtypes of α2 receptors expressed with TRPV1 in primary sensory neurons in rats. Capsaicin injected into hind paws evoked nociceptive behaviors and clonidine preinjected into the same site inhibited capsaicin-evoked responses. This inhibition was not observed when clonidine was injected into the contralateral hind paws. Preinjection of clonidine into the plantar surface of ipsilateral, but not contralateral, hind paws reduced the sensitivity to heat stimuli. Clonidine partially reduced formalin-evoked responses when it was preinjected into ipsilateral hind paws. The expression level of α2C receptor mRNA quantified by real-time PCR was highest followed by those of α2A and α2B receptors in DRGs. α2A and α2C receptor-like immunoreactivities were detected with TRPV1-like immunoreactivities in the same neurons. These results suggest that TRPV1 and α2 receptors are coexpressed in peripheral nerve terminals and that the functional association between these two molecules causes analgesia.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Clonidina/uso terapêutico , Manejo da Dor , Receptores Adrenérgicos alfa 2 , Canais de Cátion TRPV/fisiologia , Animais , Nociceptividade , Dor , Nervos Periféricos , Ratos
14.
Am J Physiol Renal Physiol ; 321(5): F587-F599, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34514879

RESUMO

Sensitization of neuronal pathways and persistent afferent drive are major contributors to somatic and visceral pain. However, the underlying mechanisms that govern whether afferent signaling will give rise to sensitization and pain are not fully understood. In the present report, we investigated the contribution of acid-sensing ion channels (ASICs) to bladder nociception in a model of chemical cystitis induced by cyclophosphamide (CYP). We found that the administration of CYP to mice lacking ASIC3, a subunit primarily expressed in sensory neurons, generates pelvic allodynia at a time point at which only modest changes in pelvic sensitivity are apparent in wild-type mice. The differences in mechanical pelvic sensitivity between wild-type and Asic3 knockout mice treated with CYP were ascribed to sensitized bladder C nociceptors. Deletion of Asic3 from bladder sensory neurons abolished their ability to discharge action potentials in response to extracellular acidification. Collectively, the results of our study support the notion that protons and their cognate ASIC receptors are part of a mechanism that operates at the nerve terminals to control nociceptor excitability and sensitization.NEW & NOTEWORTHY Our study indicates that protons and their cognate acid-sensing ion channel receptors are part of a mechanism that operates at bladder afferent terminals to control their function and that the loss of this regulatory mechanism results in hyperactivation of nociceptive pathways and the development of pain in the setting of chemical-induced cystitis.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Cistite/metabolismo , Nociceptividade , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Bexiga Urinária/inervação , Canais Iônicos Sensíveis a Ácido/genética , Potenciais de Ação , Animais , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/fisiopatologia , Micção
15.
Exp Brain Res ; 239(11): 3405-3415, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34505162

RESUMO

The nociceptive withdrawal reflex (NWR) threshold is commonly employed in the lower limb to assess clinical and experimentally induced pain. However, no studies to date have investigated changes in spinal nociception in the upper limb, via the NWR threshold, following experimentally induced central sensitization (CS). We tested the hypothesis that experimentally induced CS of the C5-C6 spinal segment significantly reduces NWR thresholds in muscles of the upper limb. Upper limb NWR thresholds from 20 young, healthy adults were assessed by applying noxious electrical stimuli to the right index finger and recording muscle activity from the biceps brachii (BI), triceps brachii (TRI), flexor carpi ulnaris (WF), and extensor carpi radialis longus (WE) muscles via surface electromyography. Topical cream (either 0.075% capsaicin, or control) was applied to the C5-C6 dermatome of the lateral forearm (50 cm2). NWR thresholds were compared at baseline, and four 10-min intervals after topical application. WF muscle NWR thresholds were significantly reduced in the capsaicin session compared to control, while TRI muscle NWR thresholds were significantly reduced 40 min after capsaicin application only (p < 0.05). There were no significant differences for BI or WE muscle NWR thresholds. We observed poor to moderate test-retest reliability for all upper limb NWR thresholds, a key contributor to the selective reduction in NWR thresholds among muscles. Accordingly, while our findings demonstrate some comparability to previously reported lower limb NWR studies, we concurrently report limitations of the upper limb NWR technique. Further exploration of optimal parameters for upper limb NWR acquisition is needed.


Assuntos
Capsaicina , Nociceptividade , Adulto , Sensibilização do Sistema Nervoso Central , Estimulação Elétrica , Eletromiografia , Humanos , Músculo Esquelético , Limiar da Dor , Reflexo , Reprodutibilidade dos Testes , Extremidade Superior
16.
Biochem Biophys Res Commun ; 574: 8-13, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34419875

RESUMO

Oxytocin is known as a social bonding hormone, but it also functions as an anxiolytic or analgesic neurotransmitter. When oxytocin regulates pain or anxiousness centrally as a neurotransmitter, it is secreted by neurons and directly projected to targeted regions. Although the function of oxytocin at the spinal level is well studied, its effects at the supraspinal level are poorly understood. We aimed to investigate the effect of oxytocin at the supraspinal level in vivo using C57BL/6J (wild-type [WT]), oxytocin-deficient (Oxt-/-), oxytocin receptor-deficient (Oxtr-/-), and oxytocin receptor-Venus (OxtrVenus/+) mice lines. Response thresholds in Oxtr-/- mice in Hargreaves and von-Frey tests were significantly lower than those in WT mice, whereas open field and light/dark tests showed no significant differences. Moreover, response thresholds in Oxt-/- mice were raised to those in WT mice after oxytocin administration. Following the Hargreaves test, we observed the co-localisation of c-fos with Venus or the oxytocin receptor in the periaqueductal gray (PAG), medial amygdala (MeA), and nucleus accumbens (NAc) regions in OxtrVenus/+ mice. Furthermore, in the PAG, MeA, and NAc regions, the co-localisation of oxytocin with c-fos and gamma-aminobutyric acid was much stronger in Oxtr-/- mice than in WT mice. However, following von-Frey test, the same findings were observed only in the MeA and NAc regions. Our results suggest that oxytocin exerts its analgesic effect on painful stimulation via the PAG region and a self-protective effect on unpleasant stimulation via the MeA and NAc regions.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Ocitocina/farmacologia , Animais , Sistema Nervoso Central/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Mol Pain ; 17: 17448069211037401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34399634

RESUMO

Chronic pain is a debilitating condition affecting millions of people worldwide, and an improved understanding of the pathophysiology of chronic pain is urgently needed. Nociceptors are the sensory neurons that alert the nervous system to potentially harmful stimuli such as mechanical pressure or noxious thermal temperature. When an injury occurs, the nociceptive threshold for pain is reduced and an increased pain signal is produced. This process is called nociceptive sensitization. This sensitization normally subsides after the injury is healed. However, dysregulation can occur which results in sensitization that persists after the injury has healed. This process is thought to perpetuate chronic pain. The Hedgehog (Hh) signaling pathway has been previously implicated in nociceptive sensitization in response to injury in Drosophila melanogaster. Downstream of Hh signaling, the Bone Morphogenetic Protein (BMP) pathway has also been shown to be necessary for this process. Here, we describe a role for nuclear components of BMP's signaling pathway in the formation of injury-induced nociceptive sensitization. Brinker (Brk), and Schnurri (Shn) were suppressed in nociceptors using an RNA-interference (RNAi) "knockdown" approach. Knockdown of Brk resulted in hypersensitivity in the absence of injury, indicating that it normally acts to suppress nociceptive sensitivity. Animals in which transcriptional activator Shn was knocked down in nociceptors failed to develop normal allodynia after ultraviolet irradiation injury, indicating that Shn normally acts to promote hypersensitivity after injury. These results indicate that Brk-related transcription regulators play a crucial role in the formation of nociceptive sensitization and may therefore represent valuable new targets for pain-relieving medications.


Assuntos
Drosophila melanogaster/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica/genética , Proteínas Hedgehog/metabolismo , Nociceptores/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
18.
J Biol Chem ; 297(3): 101085, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34411562

RESUMO

The complement cascade is a key component of the innate immune system that is rapidly recruited through a cascade of enzymatic reactions to enable the recognition and clearance of pathogens and promote tissue repair. Despite its well-understood role in immunology, recent studies have highlighted new and unexpected roles of the complement cascade in neuroimmune interaction and in the regulation of neuronal processes during development, aging, and in disease states. Complement signaling is particularly important in directing neuronal responses to tissue injury, neurotrauma, and nerve lesions. Under physiological conditions, complement-dependent changes in neuronal excitability, synaptic strength, and neurite remodeling promote nerve regeneration, tissue repair, and healing. However, in a variety of pathologies, dysregulation of the complement cascade leads to chronic inflammation, persistent pain, and neural dysfunction. This review describes recent advances in our understanding of the multifaceted cross-communication that takes place between the complement system and neurons. In particular, we focus on the molecular and cellular mechanisms through which complement signaling regulates neuronal excitability and synaptic plasticity in the nociceptive pathways involved in pain processing in both health and disease. Finally, we discuss the future of this rapidly growing field and what we believe to be the significant knowledge gaps that need to be addressed.


Assuntos
Via Clássica do Complemento/imunologia , Neuroimunomodulação/fisiologia , Dor Nociceptiva/fisiopatologia , Animais , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Humanos , Imunidade Inata/fisiologia , Neuroimunomodulação/imunologia , Plasticidade Neuronal/fisiologia , Neurônios , Nociceptividade , Dor Nociceptiva/imunologia , Dor/imunologia , Dor/fisiopatologia , Transdução de Sinais
19.
Anaesthesist ; 70(9): 735-752, 2021 09.
Artigo em Alemão | MEDLINE | ID: mdl-34424359

RESUMO

The intraoperative dosing of opioids is a challenge in routine anesthesia as the potential effects of intraoperative overdosing and underdosing are not completely understood. In recent years an increasing number of monitors were approved, which were developed for the detection of intraoperative nociception and therefore should enable a better control of opioid titration. The nociception monitoring devices use either continuous hemodynamic, galvanic or thermal biosignals reflecting the balance between parasympathetic and sympathetic activity, measure the pupil dilatation reflex or the nociceptive flexor reflex as a reflexive response to application of standardized nociceptive stimulation. This review article presents the currently available nociception monitors. Most of these monitoring devices detect nociceptive stimulations with higher sensitivity and specificity than changes in heart rate, blood pressure or sedation depth monitoring devices. There are only few studies on the effect of opioid titration guided by nociception monitoring and the possible postoperative benefits of these devices. All nociception monitoring techniques are subject to specific limitations either due to perioperative confounders (e.g. hypovolemia) or special accompanying medical conditions (e.g. muscle relaxation). There is an ongoing discussion about the clinical relevance of nociceptive stimulation in general anesthesia and the effect on patient outcome. Initial results for individual monitor systems show a reduction in opioid consumption and in postoperative pain level. Nevertheless, current evidence does not enable the routine use of nociception monitoring devices to be recommended as a clear beneficial effect on long-term outcome has not yet been proven.


Assuntos
Analgesia , Analgésicos Opioides , Anestesia Geral , Humanos , Monitorização Intraoperatória , Nociceptividade
20.
J Neurosci ; 41(36): 7546-7560, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34353899

RESUMO

Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain.SIGNIFICANCE STATEMENT It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of CaV2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral CaV2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of CaV2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related CaV2.1 channels. Our findings suggest that interrupting CaV2.2-dependent calcium entry in skin might reduce heat hypersensitivity that develops after noxious heat exposure and may limit the degree of heat hypersensitivity associated with certain other forms of pain.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Cálcio/metabolismo , Hiperalgesia/metabolismo , Neurônios/fisiologia , Nociceptores/fisiologia , Terminações Pré-Sinápticas/metabolismo , Pele/inervação , Corno Dorsal da Medula Espinal/metabolismo , Animais , Temperatura Alta , Camundongos , Nociceptividade/fisiologia , Estimulação Física , Pele/metabolismo , Transmissão Sináptica/fisiologia
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