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1.
J Neurosci ; 41(39): 8210-8219, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34408066

RESUMO

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENT In this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics, and persistent pain models to study how tissue injury alters the sensation of temperature. We discover modality-specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bidirectional change of thermosensitivity by injury and suggests that the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception toward a unique thermal modality that was observed clinically in chronic pain patients.


Assuntos
Hiperalgesia/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Sensação Térmica/fisiologia , Animais , Antineoplásicos/farmacologia , Cálcio/metabolismo , Formaldeído/farmacologia , Camundongos , Camundongos Transgênicos , Oxaliplatina/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Temperatura , Sensação Térmica/efeitos dos fármacos
2.
PLoS One ; 16(7): e0254497, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34310642

RESUMO

The aim of the study was to evaluate the analgesic efficacy of tramadol compared to butorphanol administered locally in ventral surface of the hind paw of rats. Prospective, randomized experimental study; twenty-one adult male Wistar rats were selected. Heart rate (beats minute-1), respiratory rate (breaths minute-1), and paw withdrawal latency (onset of radiant heat until paw withdrawal/seconds) were measured prior (T0) and after (T5, T10, T15, T20) intraplantar injection with saline solution 0,9% (group S), butorphanol 1 mg kg-1 (group B), and tramadol 1 mg kg-1 (group T). Shapiro-Wilk normality test and Friedman test were used to analyze the data expressed by median and range. Statistical significance was set at p < 0.05. Statistical analysis of heart rate showed that there were significant differences between groups at different monitoring times. There were no significant differences in respiratory rate after intraplantar injection in any of the treatment groups. The paw withdrawal latency values at T5, T10, and T15 minutes after intraplantar injection in the group B were significantly higher compared to baseline value and to the values of the other groups. The paw withdrawal latency were no significant changes in the measurements of intragroup in S and T. Intraplantar administration of butorphanol provides a good analgesia and significantly increases paw withdrawal latency compared to tramadol. Intraplantar injection of butorphanol could be useful and safe and safe technique to achieve local analgesia for minor surgical procedures in rats.


Assuntos
Analgésicos Opioides/farmacologia , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Tramadol/farmacologia , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Butorfanol/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hiperalgesia/fisiopatologia , Dor/fisiopatologia , Ratos , Ratos Wistar , Taxa Respiratória/efeitos dos fármacos
3.
PLoS One ; 16(7): e0254790, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34329326

RESUMO

The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).


Assuntos
Analgésicos/uso terapêutico , Queimaduras , Hiperalgesia , Modelos Biológicos , Dor , Queimaduras/tratamento farmacológico , Queimaduras/fisiopatologia , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor
4.
PLoS Biol ; 19(7): e3001337, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34292944

RESUMO

Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Encéfalo/metabolismo , Hiperalgesia/fisiopatologia , Microglia/metabolismo , Plasticidade Neuronal/fisiologia , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Camundongos Knockout , Traumatismos dos Nervos Periféricos/fisiopatologia
5.
Sci Rep ; 11(1): 15434, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326451

RESUMO

This study aimed to verify if migraine frequency or migraine-associated neck pain were associated with a reduction of normalized force and altered electromyographic activity during maximal cervical muscle isometric contractions. Additionally, it aimed to assess the correlation of normalized isometric force with years with migraine, headache frequency, headache intensity, migraine-related disability, and severity of cutaneous allodynia. The sample comprises 71 women with migraine (40/31 episodic/chronic, 42/18 with/without neck pain) and 32 women without headache. Cervical muscle isometric force in flexion, extension, and lateral flexion was assessed synchronized with the acquisition of superficial electromyography from the cervical muscles. Women with episodic migraine presented lower normalized isometric force in extension, flexion, and right and left lateral flexions than controls (P < 0.05). Women with migraine and neck pain exhibited lower cervical extension and right/left lateral-flexions normalized isometric force than controls (P < 0.05). No significant differences were observed in antagonist activity. Normalized isometric force in all directions showed weak to moderate correlations with the severity of self-reported symptoms of cutaneous allodynia (- 0.25 ≥ r ≥ - 0.39). No additional linear correlation with clinical migraine features was observed. In conclusion, cervical muscle weakness may be associated with episodic migraine and neck pain concurrent with migraine attacks without altered antagonist activity. Additionally, it may also be related to the severity of cutaneous allodynia.


Assuntos
Contração Isométrica , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/fisiopatologia , Músculos do Pescoço/fisiopatologia , Cervicalgia/complicações , Cervicalgia/fisiopatologia , Adulto , Estudos de Casos e Controles , Eletromiografia/métodos , Feminino , Cefaleia/fisiopatologia , Humanos , Hiperalgesia/fisiopatologia , Pessoa de Meia-Idade , Autorrelato , Adulto Jovem
6.
Anesth Analg ; 133(3): 794-810, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166321

RESUMO

BACKGROUND: Remifentanil can induce postinfusion cold hyperalgesia. N-methyl-d-aspartate receptor (NMDAR) activation and upregulation of transient receptor potential melastatin 8 (TRPM8) membrane trafficking in dorsal root ganglion (DRG) are critical to cold hyperalgesia derived from neuropathic pain, and TRPM8 activation causes NMDAR-dependent cold response. Contribution of P2Y1 purinergic receptor (P2Y1R) activation in DRG to cold pain hypersensitivity and NMDAR activation induced by P2Y1R upregulation in neurons are also unraveled. This study explores whether P2Y1R contributes to remifentanil-induced cold hyperalgesia via TRPM8-dependent regulation of NMDAR phosphorylation in DRG. METHODS: Rats with remifentanil-induced cold hyperalgesia were injected with TRPM8 antagonist or P2Y1R antagonist at 10 minutes before remifentanil infusion. Cold hyperalgesia (paw lift number and withdrawal duration on cold plate) was measured at -24, 2, 6, 24, and 48 hours following remifentanil infusion. After the last behavioral test, P2Y1R expression, TRPM8 expression and membrane trafficking, and NMDAR subunit (NR1 and NR2B) expression and phosphorylation in DRG were detected by western blot, and colocalization of P2Y1R with TRPM8 was determined by double-labeling immunofluorescence. Two-way repeated measures analysis of variance (ANOVA) or 2 × 2 factorial design ANOVA with repeated measures was used to analyze behavioral data of cold hyperalgesia. One-way ANOVA followed by Bonferroni post hoc comparisons was used to analyze the data in western blot and immunofluorescence. RESULTS: Remifentanil infusion (1 µg·kg-1·min-1 for 60 minutes) induced cold hyperalgesia (hyperalgesia versus control, paw lift number and withdrawal duration on cold plate at 2-48 hours, P < .0001) with upregulated NR1 (hyperalgesia versus naive, 48 hours, mean ± standard deviation [SD], 114.00% ± 12.48% vs 41.75% ± 5.20%, P < .005) and NR2B subunits expression (104.13% ± 8.37% vs 24.63% ± 4.87%, P < .005), NR1 phosphorylation at Ser896 (91.88% ± 7.08% vs 52.00% ± 7.31%, P < .005) and NR2B phosphorylation at Tyr1472 (115.75% ± 8.68% vs 59.75% ± 7.78%, P < .005), TRPM8 expression (115.38% ± 9.27% vs 40.50% ± 4.07%, P < .005) and membrane trafficking (112.88% ± 5.62% vs 48.88% ± 6.49%, P < .005), and P2Y1R expression (128.25% ± 14.86% vs 45.13% ± 7.97%, P < .005) in DRG. Both TRPM8 and P2Y1R antagonists attenuated remifentanil-induced cold hyperalgesia and downregulated increased NR1 and NR2B expression and phosphorylation induced by remifentanil (remifentanil + RQ-00203078 versus remifentanil + saline, NR1 phosphorylation, 69.38% ± 3.66% vs 92.13% ± 4.85%; NR2B phosphorylation, 72.25% ± 6.43% vs 111.75% ± 11.00%, P < .0001). NMDAR activation abolished inhibition of TRPM8 and P2Y1R antagonists on remifentanil-induced cold hyperalgesia. P2Y1R antagonist inhibited remifentanil-evoked elevations in TRPM8 expression and membrane trafficking and P2Y1R-TRPM8 coexpression (remifentanil + 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate [MRS2179] versus remifentanil + saline, coexpression, 8.33% ± 1.33% vs 22.19% ± 2.15%, P < .0001). CONCLUSIONS: Attenuation of remifentanil-induced cold hyperalgesia by P2Y1R inhibition is attributed to downregulations in NMDAR expression and phosphorylation via diminishing TRPM8 expression and membrane trafficking in DRG.


Assuntos
Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Limiar da Dor , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Canais de Cátion TRPM/metabolismo , Analgésicos/farmacologia , Animais , Comportamento Animal , Temperatura Baixa , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Limiar da Dor/efeitos dos fármacos , Fosforilação , Transporte Proteico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/efeitos dos fármacos , Remifentanil , Transdução de Sinais , Canais de Cátion TRPM/antagonistas & inibidores
7.
Elife ; 102021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061020

RESUMO

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aß primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hiperalgesia/metabolismo , Interneurônios/metabolismo , Mecanotransdução Celular , Limiar da Dor , Células do Corno Posterior/metabolismo , Animais , Comportamento Animal , Peptídeo Relacionado com Gene de Calcitonina/genética , Modelos Animais de Doenças , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Estimulação Física , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
8.
Sci Rep ; 11(1): 13277, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168249

RESUMO

Nerves are subjected to tensile forces in various paradigms such as injury and regeneration, joint movement, and rehabilitation treatments, as in the case of neurodynamic treatment (NDT). The NDT induces selective uniaxial repeated tension on the nerve and was described to be an effective treatment to reduce pain in patients. Nevertheless, the biological mechanisms activated by the NDT promoting the healing processes of the nerve are yet still unknown. Moreover, a dose-response analysis to define a standard protocol of treatment is unavailable. In this study, we aimed to define in vitro whether NDT protocols could induce selective biological effects on sensory and motor neurons, also investigating the possible involved molecular mechanisms taking a role behind this change. The obtained results demonstrate that NDT induced significant dose-dependent changes promoting cell differentiation, neurite outgrowth, and neuron survival, especially in nociceptive neurons. Notably, NDT significantly upregulated PIEZO1 gene expression. A gene that is coding for an ion channel that is expressed both in murine and human sensory neurons and is related to mechanical stimuli transduction and pain suppression. Other genes involved in mechanical allodynia related to neuroinflammation were not modified by NDT. The results of the present study contribute to increase the knowledge behind the biological mechanisms activated in response to NDT and to understand its efficacy in improving nerve regenerational physiological processes and pain reduction.


Assuntos
Neurônios Motores/fisiologia , Modalidades de Fisioterapia , Células Receptoras Sensoriais/fisiologia , Apoptose , Linhagem Celular , Expressão Gênica , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Técnicas In Vitro , Neurônios Motores/metabolismo , Células Receptoras Sensoriais/metabolismo
9.
Neurology ; 97(4): e389-e402, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34011572

RESUMO

OBJECTIVE: To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms. METHODS: We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area. RESULTS: Among 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function. CONCLUSION: Mechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients.


Assuntos
Hiperalgesia/fisiopatologia , Neuralgia/fisiopatologia , Percepção da Dor/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Radiculopatia/fisiopatologia , Feminino , Humanos , Hiperalgesia/complicações , Masculino , Neuralgia/etiologia , Medição da Dor , Limiar da Dor/fisiologia , Traumatismos dos Nervos Periféricos/complicações , Estimulação Física , Radiculopatia/complicações
10.
Phys Ther ; 101(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989399

RESUMO

OBJECTIVE: The presence of altered nociceptive pain processing in patients with upper extremity tendinopathy/overuse injury is conflicting. Our aim was to compare pressure pain thresholds (PPTs) in symptomatic and distant pain-free areas between patients with upper extremity tendinopathy/overuse injury and controls. METHODS: Five databases were searched from inception to October 15, 2020. The authors selected case-control studies comparing PPTs between individuals with upper extremity tendinopathy/overuse injury and pain-free controls. Data were extracted for population, diagnosis, sample size, outcome, and type of algometer. Results were extracted by 3 reviewers. The methodological quality/risk of bias (Newcastle-Ottawa Quality Assessment Scale) and evidence level (Grading of Recommendations Assessment, Development and Evaluation approach) were assessed. Meta-analyses of symptomatic, segment-related, and distant pain-free areas were compared. RESULTS: The search identified 807 publications with 19 studies (6 shoulder, 13 elbow) eligible for inclusion. The methodological quality ranged from fair (48%) to good (37%). Patients exhibited lower bilateral PPTs than controls at the symptomatic area (affected side: MD = -175.89 kPa [95% CI = -220.30 to -131.48 kPa]; nonaffected side: MD = -104.50 kPa [95% CI = -142.72 to -66.28 kPa]) and the segment-related area (affected side: MD = -150.63 kPa [95% CI = -212.05 to -89.21 kPa]; nonaffected side: MD = -170.34 kPa [95% CI = - 248.43 to -92.25]) than controls. No significant differences in PPTs over distant pain-free areas were observed. CONCLUSION: Low to moderate quality evidence suggests bilateral hypersensitivity to pressure pain at the symptomatic and contralateral/mirror areas in patients with upper extremity tendinopathies/overuse injury. Moderate quality of evidence supports bilateral pressure pain sensitivity in the segment-related area (neck) in lateral epicondylalgia, but not in subacromial impingement syndrome. No evidence of widespread pressure pain hyperalgesia was reported. IMPACT: Early identification of people with altered pain modulation could guide clinicians in treatment strategies. This review shows that there is a complex interplay between peripheral and central pain mechanisms in upper extremity tendinopathies/overuse injuries and that there likely are different subgroups of patients with upper extremity conditions.


Assuntos
Transtornos Traumáticos Cumulativos/fisiopatologia , Hiperalgesia/fisiopatologia , Limiar da Dor/fisiologia , Tendinopatia/fisiopatologia , Extremidade Superior/fisiopatologia , Humanos
11.
J Neurosci ; 41(26): 5595-5619, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34031166

RESUMO

Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aß slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aß SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Using a genetic Merkel cell KO mouse model, we subsequently examined the importance of intact Merkel cell-Aß complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that, in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Aß afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex-dependent manner.SIGNIFICANCE STATEMENT Merkel discs or Merkel cell-Aß afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-Aß afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.


Assuntos
Hiperalgesia/fisiopatologia , Células de Merkel/fisiologia , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Caracteres Sexuais , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/etiologia , Neurônios Aferentes/fisiologia , Traumatismos dos Nervos Periféricos/complicações , Pele/inervação , Nervo Sural/lesões
13.
Sci Rep ; 11(1): 9807, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963251

RESUMO

This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.


Assuntos
Ritmo alfa , Encéfalo/fisiopatologia , Hiperalgesia/fisiopatologia , Efeito Nocebo , Adolescente , Adulto , Feminino , Humanos , Masculino , Dor
14.
Neurochem Res ; 46(8): 2143-2153, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34014488

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1ß and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1ß and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.


Assuntos
Gânglios Espinais/metabolismo , Síndromes de Compressão Nervosa/fisiopatologia , Neuralgia/fisiopatologia , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/metabolismo , Animais , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Morfolinas/farmacologia , Síndromes de Compressão Nervosa/tratamento farmacológico , Neuralgia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirróis/farmacologia , Ratos Wistar , Corantes de Rosanilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores
15.
Front Immunol ; 12: 626884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897685

RESUMO

Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits via both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.


Assuntos
Artrite Experimental/fisiopatologia , Microglia/fisiologia , Neurônios Aferentes/fisiologia , Medula Espinal/fisiopatologia , Trifosfato de Adenosina/fisiologia , Animais , Artralgia/terapia , Modelos Animais de Doenças , Feminino , Hiperalgesia/fisiopatologia , Ácido Iodoacético/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
16.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1093-G1104, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908261

RESUMO

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.


Assuntos
Motilidade Gastrointestinal/fisiologia , Hiperalgesia/fisiopatologia , Morfina/farmacologia , Constipação Induzida por Opioides/fisiopatologia , Animais , Ciclo-Oxigenase 2/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Hiperalgesia/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Constipação Induzida por Opioides/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
17.
Diabetes Res Clin Pract ; 176: 108790, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33812900

RESUMO

AIMS: The pathophysiological alteration of diabetic neuropathic pain (DNP) in brain is unclear. Here we aimed to explore the metabolomic characteristics of brain in rats over the progression of DNP through metabolomic analysis. METHODS: Adult rats were randomly divided into control group and DNP group. Body weight, blood glucose and behavioral assessment of neuropathic pain were measured every week after streptozotocin (STZ) injection. Finally, the brains of 2 rats from control group and 6 rats from DNP group were removed every 4 weeks after STZ injection for metabolomics analysis. RESULTS: After 4 weeks of STZ-injection, the rats with diabetes developed DNP, which was characterized as mechanical allodynia and thermal nociception. As for metabolomic analysis, differentially expressed metabolites (DE metabolites) showed a dynamic alteration over the development of DNP and affected several KEGG pathways associated with amino acid metabolism. Furthermore, the expression of l-Threonine, l-Methionine, d-Proline, l-Lysine and N-Acetyl-l-alanine were significantly decreased at all time points of DNP group. The amino acids which were precursor of analgesic neurotransmitters were downregulated over the progression of DNP, including l-tryptophan, l-histidine and l-tyrosine. CONCLUSIONS: The impairment of amino acid metabolism in brain might contribute to the progression of DNP through decreasing analgesic neurotransmitters.


Assuntos
Aminoácidos/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/etiologia , Neuralgia/etiologia , Aminoácidos/análise , Aminoácidos/fisiologia , Animais , Química Encefálica/fisiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Hiperalgesia/complicações , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Metabolômica , Neuralgia/metabolismo , Neuralgia/patologia , Ratos , Ratos Sprague-Dawley , Estreptozocina
18.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806315

RESUMO

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Experimental/terapia , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite/terapia , Manejo da Dor/métodos , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Cartilagem Articular/patologia , Relação Dose-Resposta Imunológica , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Injeções Intra-Articulares , Ácido Iodoacético/toxicidade , Masculino , Fator de Crescimento Neural/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Ratos , Ratos Sprague-Dawley , Suporte de Carga/fisiologia
19.
Eur J Pharmacol ; 899: 174008, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705800

RESUMO

Neuropathic pain is a debilitating chronic pain condition, and its treatment remains a clinical challenge. Curcumin, a naturally occurring phenolic compound, possesses diverse biological and pharmacological effects but has not yet been approved as a drug due to its low bioavailability. In order to overcome this limitation, we synthesized a potential ester prodrug of curcumin, curcumin diethyl diglutarate (CurDDG). In this study, we evaluated the pharmacological advantages of CurDDG over curcumin in a mouse model of chronic constriction injury (CCI), and the anti-inflammatory effect of CurDDG in LPS-induced RAW 264.7 macrophage cells was accessed to clarify the underline mechanism. Mice were treated with various oral doses of curcumin (25, 50, 100 and 200 mg/kg/day, daily for 14 days) or equimolar doses of CurDDG. CurDDG at all doses tested significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia compared with the CCI-control group. CurDDG at 25, 50 and 100 mg/kg demonstrated significantly greater efficacy on both mechanical and thermal hypersensitivities compared to that of curcumin. The effect of CurDDG correlated well with the inhibition of TNF-α and IL-6 levels in both the sciatic nerve and the spinal cord, as compared to its respective control groups. Similarly, in the in vitro study, CurDDG significantly reduced the LPS-induced expression of TNF-α and IL-6. Moreover, CurDDG significantly decreased COX-2 and iNOS levels and attenuated p38, JNK, and ERK1/2 phosphorylation as compared to the curcumin-treated cells. Altogether, this study demonstrated the improved pharmacological effects of curcumin by its diglutarate conjugate, CurDDG.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Glutaratos/farmacologia , Hiperalgesia/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Pró-Fármacos/farmacologia , Nervo Isquiático/efeitos dos fármacos , Ciática/prevenção & controle , Medula Espinal/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Células RAW 264.7 , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Ciática/metabolismo , Ciática/fisiopatologia , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Succinatos , Fator de Necrose Tumoral alfa/metabolismo
20.
Inflamm Res ; 70(4): 483-493, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33715021

RESUMO

BACKGROUND: Early life experience can cause long-term alterations in the nociceptive processes underlying chronic pain, but the consequences of early life arthritic joint inflammation upon the sensory innervation of the joint is not known. Here, we measure pain sensitivity and sensory innervation in a young, juvenile and adult rodent model of arthritic joints and test the consequences of joint inflammation in young animals upon adult arthritic pain and joint innervation. METHODS: Unilateral ankle joint injections of complete Freund's adjuvant (CFA) (6-20 µl) were performed in young, postnatal day (P)8, adolescent (P21) and adult (P40) rats. A separate cohort of animals were injected at P8, and again at P40. Hindpaw mechanical sensitivity was assessed using von Frey monofilaments (vF) for 10 days. Nerve fibres were counted in sections through the ankle joint immunostained for calcitonin gene-related peptide (CGRP) and neurofilament 200 kDa (NF200). RESULTS: Ankle joint CFA injection increased capsular width at all ages. Significant mechanical pain hypersensitivity and increased number of joint CGRP + ve sensory fibres occurred in adolescent and adult, but not young, rats. Despite the lack of acute reaction, joint inflammation at a young age resulted in significantly increased pain hypersensitivity and CGRP+ fibre counts when the rats were re-inflamed as adults. CONCLUSIONS: Joint inflammation increases the sensory nociceptive innervation and induces acute pain hypersensitivity in juvenile and adult, but not in young rats. However, early life joint inflammation 'primes' the joint such that adult inflammatory pain behaviour and nociceptive nerve endings in the joint are significantly increased. Early life joint inflammation may be an important factor in the generation and maintenance of chronic arthritic pain.


Assuntos
Articulação do Tornozelo/inervação , Artrite/fisiopatologia , Hiperalgesia/fisiopatologia , Dor/fisiopatologia , Envelhecimento/fisiologia , Animais , Articulação do Tornozelo/metabolismo , Articulação do Tornozelo/fisiologia , Artrite/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund , Hiperalgesia/metabolismo , Injeções Intra-Articulares , Masculino , Fibras Nervosas , Proteínas de Neurofilamentos/metabolismo , Dor/metabolismo , Medição da Dor , Ratos Sprague-Dawley , Tato
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