RESUMEN
ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.
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Epilepsia del Lóbulo Temporal , Hipocampo , Imagen por Resonancia Magnética , Umbral del Dolor , Humanos , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Femenino , Adulto , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/complicaciones , Umbral del Dolor/fisiología , Persona de Mediana Edad , Dimensión del Dolor/métodos , Adulto Joven , Hiperalgesia/fisiopatología , Hiperalgesia/patología , Dolor/fisiopatología , Dolor/patología , Dolor/diagnóstico por imagen , Estimulación FísicaRESUMEN
The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67µM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100µl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100µl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter.
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Furosemida , Ganglios Espinales , Voluntarios Sanos , Hiperalgesia , Miembro 2 de la Familia de Transportadores de Soluto 12 , Ácido gamma-Aminobutírico , Humanos , Animales , Ratones , Ácido gamma-Aminobutírico/metabolismo , Masculino , Adulto , Furosemida/farmacología , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Femenino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Dolor Agudo/metabolismo , Dolor Agudo/fisiopatología , Calcio/metabolismo , Receptores de GABA-A/metabolismo , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/fisiopatología , Adulto JovenRESUMEN
Pain is a crucial protective mechanism for the body. It alerts us to potential tissue damage or injury and promotes the avoidance of harmful stimuli. Injury-induced inflammation and tissue damage lead to pain sensitization, which amplifies responses to subsequent noxious stimuli even after an initial primary injury has recovered. This phenomenon, commonly referred to as hyperalgesic priming, was investigated in male and female mice to determine whether it is specific to the site of previous injury. We used 10µl of 50 % Freund's complete adjuvant (CFA) administered to the left hind paw as a model of peripheral injury. Both male and female mice exhibited robust site-specific mechanical hypersensitivity after CFA, which resolved within one-week post-injection. After injury resolution, only male CFA-primed mice showed enhanced and prolonged mechanical sensitivity in response to a chemical challenge or a single 0.5 mA electric footshock. Among CFA-primed male mice, shock-induced mechanical hypersensitivity was expressed in both the left (previously injured) and the right (uninjured) hind paws, suggesting a pivotal role for altered centralized processes in the expression of pain sensitization. These findings indicate that pain history regulates sensory responses to subsequent mechanical and chemical pain stimuli in a sex-specific manner-foot-shock-induced hyperalgesic priming expression among male mice generalized beyond the initial injury site.
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Adyuvante de Freund , Hiperalgesia , Inflamación , Animales , Masculino , Femenino , Hiperalgesia/fisiopatología , Hiperalgesia/etiología , Inflamación/inducido químicamente , Ratones , Modelos Animales de Enfermedad , Dolor/etiología , Dolor/fisiopatología , Ratones Endogámicos C57BL , Umbral del Dolor/fisiología , Caracteres Sexuales , Factores Sexuales , Dimensión del DolorRESUMEN
Neuropathic pain (NP) is pain resulting from lesions or disease of the somatosensory system. A cardinal feature of NP is tactile allodynia (a painful response to normally innocuous stimulation). In 2003, a breakthrough strategy for inducing NP was proposed in which microglia of the spinal dorsal horn (SDH) are activated after peripheral nerve injury (PNI) to overexpress P2X4 receptor (P2X4R) and play an important role in inducing tactile allodynia. In 2005, it was reported that stimulation of microglial P2X4Rs evokes the release of brain-derived neurotrophic factor (BDNF), which causes a depolarizing shift of the anion reversal potential (Eanion) of secondary sensory neurons. These findings and other facts suggest the mechanism by which innocuous touch stimuli cause severe pain and the important role of microglia in the mechanism.
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Factor Neurotrófico Derivado del Encéfalo , Microglía , Neuralgia , Receptores Purinérgicos P2X4 , Microglía/metabolismo , Neuralgia/metabolismo , Neuralgia/fisiopatología , Humanos , Animales , Receptores Purinérgicos P2X4/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Traumatismos de los Nervios Periféricos/metabolismoRESUMEN
BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
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Modelos Animales de Enfermedad , Ratones Noqueados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Receptores de Tipo II del Péptido Intestinal Vasoactivo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/genética , Ratones , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Hiperalgesia/fisiopatología , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ratones Endogámicos C57BL , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Miembro Posterior/fisiopatologíaRESUMEN
INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.
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Modelos Animales de Enfermedad , Hiperalgesia , Neuralgia , Neuroma , Animales , Masculino , Neuroma/patología , Neuralgia/fisiopatología , Neuralgia/patología , Neuralgia/etiología , Femenino , Hiperalgesia/fisiopatología , Hiperalgesia/patología , Ratas Sprague-Dawley , Ratas , Nervio Tibial/patología , Nervio Tibial/fisiopatología , Dimensión del Dolor/métodosRESUMEN
OBJECTIVE: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. BACKGROUND: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. METHODS: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. RESULTS: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. CONCLUSIONS: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.
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Modelos Animales de Enfermedad , Trastornos Migrañosos , Nitroglicerina , Animales , Nitroglicerina/farmacología , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Masculino , Femenino , Ratones , Hiperalgesia/fisiopatología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones Endogámicos C57BL , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiopatología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Proteínas de Unión al Calcio/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Emociones/fisiología , Emociones/efectos de los fármacos , Proteínas de Microfilamentos/metabolismo , Vasodilatadores/farmacología , Enfermedad Crónica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Núcleo Caudal del Trigémino/efectos de los fármacos , Núcleo Caudal del Trigémino/metabolismoRESUMEN
BACKGROUND: Total knee replacement (TKR) is the gold standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. METHODS: This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6 and 12 months post-TKR. We assessed preoperative and postoperative (3 and 6 months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM) and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia and temporal summation to repeated pinprick stimulation. RESULTS: Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial knee undergoing TKR, and cuff pressure at the calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with preoperative KOA pain intensity. Moreover, preoperative pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6 and 12 months respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up. CONCLUSION: Our findings suggest that preoperative pinprick hyperalgesia and neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain. SIGNIFICANCE STATEMENT: This study's findings hold significant implications for chronic pain management in knee osteoarthritis patients, particularly those undergoing total knee replacement surgery (TKR). Mechanical hyperalgesia and neuropathic pain-like characteristics predict postoperative pain 1 year after TKR, emphasizing the importance of understanding pain phenotypes in OA for selecting appropriate pain management strategies. The normalization of hyperalgesia after surgery correlates with better long-term outcomes, further highlighting the therapeutic potential of addressing abnormal pain processing mechanisms pre- and post-TKR.
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Artroplastia de Reemplazo de Rodilla , Hiperalgesia , Neuralgia , Osteoartritis de la Rodilla , Dimensión del Dolor , Umbral del Dolor , Dolor Postoperatorio , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Hiperalgesia/fisiopatología , Hiperalgesia/etiología , Hiperalgesia/diagnóstico , Masculino , Neuralgia/etiología , Neuralgia/diagnóstico , Femenino , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/etiología , Anciano , Persona de Mediana Edad , Osteoartritis de la Rodilla/cirugía , Dimensión del Dolor/métodos , PronósticoRESUMEN
Hand-holding reduces experimentally induced acute pain and buffers against the development of mechanical secondary hypersensitivity, an indirect proxy of central sensitization. Here, we tested if verbal support from a stranger, a common occurrence in clinical contexts, exerts the same effects. In this preregistered study, 44 healthy female participants were assigned to an alone or support group whereby a supportive female stranger encouraged them through the painful procedure leading to secondary mechanical hypersensitivity. Mechanical hypersensitivity was measured via self-reports and by the size of the anteroposterior and mediolateral spread of mechanical hypersensitivity. We investigated the moderating role of attachment style on self-reports and the effects of support on skin conductance level, salivary cortisol, and pinprick-evoked potentials. We also tested whether theta/beta ratio in the resting-state electroencephalogram predicted mechanical hypersensitivity. Self-reported ratings and the late part of the pinprick-evoked potentials were reduced in the support group, but the spread of mechanical hypersensitivity was not. Attachment anxiety and avoidance moderated the self-reported intensity such that individuals with higher attachment anxiety and avoidance scores reported lower intensity ratings in the support group. No significant effect of the verbal support was observed on skin conductance level and salivary cortisol. The theta/beta ratio did not predict the extent of hypersensitivity. Our data indicate that, in women, verbal support during intense pain leading to hypersensitivity is effective on some behavioral outcomes, but altogether the lack of group differences in cortisol, self-reported stress, and skin conductance does not provide strong support for the stress-buffering hypothesis. PERSPECTIVE: Verbal support by a stranger during a painful procedure leading to secondary mechanical hypersensitivity attenuated the development of some measures of mechanical hypersensitivity and associated neural responses in healthy female participants. No evidence was found for the role of stress. DATA AVAILABILITY: The authors will make all data available upon request.
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Hidrocortisona , Hiperalgesia , Humanos , Femenino , Adulto , Adulto Joven , Hiperalgesia/fisiopatología , Hidrocortisona/metabolismo , Electroencefalografía , Apego a Objetos , Respuesta Galvánica de la Piel/fisiología , Autoinforme , Dimensión del Dolor , Saliva/metabolismo , Saliva/químicaRESUMEN
Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.
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Modelos Animales de Enfermedad , Neuralgia , Nervios Espinales , Animales , Neuralgia/patología , Neuralgia/fisiopatología , Neuralgia/etiología , Ligadura/métodos , Ligadura/efectos adversos , Ratas , Ratones , Hiperalgesia/fisiopatología , Dimensión del Dolor/métodos , MasculinoRESUMEN
OBJECTIVE: To explore and characterize somatosensory dysfunction in patients with post-polio syndrome and chronic pain, by conducting examinations with Quantitative Sensory Testing. DESIGN: A cross-sectional, descriptive, pilot study conducted during 1 month. SUBJECTS/PATIENTS: Six patients with previously established post-polio syndrome and related chronic pain. METHODS: All subjects underwent a neurological examination including neuromuscular function, bedside sensory testing, a thorough pain anamnesis, and pain drawing. Screening for neuropathic pain was done with 2 questionnaires. A comprehensive Quantitative Sensory Testing battery was conducted with z-score transformation of obtained data, enabling comparison with published reference values and the creation of sensory profiles, as well as comparison between the study site (more polio affected extremity) and internal control site (less affected extremity) for each patient. RESULTS: Derived sensory profiles showed signs of increased prevalence of sensory aberrations compared with reference values, especially Mechanical Pain Thresholds, with significant deviation from reference data in 5 out of 6 patients. No obvious differences in sensory functions were seen between study sites and internal control sites. CONCLUSION: Post-polio syndrome may be correlated with a mechanical hyperalgesia/allodynia and might be correlated to a somatosensory dysfunction. With lack of evident side-to-side differences, the possibility of a generalized dysfunction in the somatosensory system might be considered.
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Síndrome Pospoliomielitis , Humanos , Síndrome Pospoliomielitis/fisiopatología , Síndrome Pospoliomielitis/complicaciones , Proyectos Piloto , Estudios Transversales , Femenino , Masculino , Persona de Mediana Edad , Anciano , Dimensión del Dolor , Umbral del Dolor/fisiología , Dolor Crónico/fisiopatología , Dolor Crónico/etiología , Dolor Crónico/diagnóstico , Trastornos Somatosensoriales/etiología , Trastornos Somatosensoriales/fisiopatología , Trastornos Somatosensoriales/diagnóstico , Adulto , Examen Neurológico/métodos , Hiperalgesia/fisiopatología , Hiperalgesia/diagnóstico , Neuralgia/etiología , Neuralgia/diagnóstico , Neuralgia/fisiopatologíaRESUMEN
The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.
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Ácido Glutámico , Hiperalgesia , Neuronas , Núcleo Accumbens , Área Tegmental Ventral , Animales , Masculino , Hiperalgesia/fisiopatología , Área Tegmental Ventral/fisiopatología , Ratones , Ácido Glutámico/metabolismo , Núcleo Accumbens/fisiopatología , Neuronas/metabolismo , Mesencéfalo , Ratones Endogámicos C57BL , Resiliencia Psicológica , Habénula , Modelos Animales de EnfermedadRESUMEN
An intriguing perspective about human emotion, the theory of constructed emotion considers emotions as generative models according to the Bayesian brain hypothesis. This theory brings fresh insight to existing findings, but its complexity renders it challenging to test experimentally. We argue that laboratory studies of pain could support the theory because although some may not consider pain to be a genuine emotion, the theory must at minimum be able to explain pain perception and its dysfunction in pathology. We review emerging evidence that bear on this question. We cover behavioral and neural laboratory findings, computational models, placebo hyperalgesia, and chronic pain. We conclude that there is substantial evidence for a predictive processing account of painful experience, paving the way for a better understanding of neuronal and computational mechanisms of other emotions.
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Teorema de Bayes , Emociones , Percepción del Dolor , Humanos , Emociones/fisiología , Percepción del Dolor/fisiología , Encéfalo/fisiología , Dolor/psicología , Dolor/fisiopatología , Hiperalgesia/fisiopatología , Hiperalgesia/psicología , Dolor Crónico/psicología , Dolor Crónico/fisiopatologíaRESUMEN
BACKGROUND: Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. METHODS: By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. RESULTS: We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. CONCLUSION: The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.
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Neuralgia , Tractos Piramidales , Accidente Cerebrovascular , Animales , Neuralgia/etiología , Neuralgia/fisiopatología , Masculino , Accidente Cerebrovascular/complicaciones , Neuronas , Hiperalgesia/fisiopatología , Hiperalgesia/etiología , Ratas Sprague-Dawley , Ratas , Modelos Animales de Enfermedad , Médula EspinalRESUMEN
Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at 6 months and differentiated how pain and disability changed over time. Participants with acute nonspecific LBP (<6 weeks after pain onset, N = 118) were included in this longitudinal study. Quantitative sensory testing, including pressure and heat pain thresholds, and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at 3 and 6 months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N = 50) and unrecovered (N = 68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N = 19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at 6 months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP does not precede poor recovery. High psychological distress in acute LBP has a stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes.
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Dolor Agudo , Dolor Crónico , Dolor de la Región Lumbar , Umbral del Dolor , Humanos , Dolor de la Región Lumbar/psicología , Dolor de la Región Lumbar/fisiopatología , Dolor de la Región Lumbar/complicaciones , Masculino , Femenino , Adulto , Estudios Longitudinales , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Persona de Mediana Edad , Dolor Agudo/fisiopatología , Dolor Agudo/psicología , Análisis por Conglomerados , Umbral del Dolor/fisiología , Dimensión del Dolor , Hiperalgesia/fisiopatología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Distrés Psicológico , Adulto JovenRESUMEN
The introduction of sex-as-a-biological-variable policies at funding agencies around the world has led to an explosion of very recent observations of sex differences in the biology underlying pain. This review considers evidence of sexually dimorphic mechanisms mediating pain hypersensitivity, derived from modern assays of persistent pain in rodent animal models. Three well-studied findings are described in detail: the male-specific role of spinal cord microglia, the female-specific role of calcitonin gene-related peptide (CGRP), and the female-specific role of prolactin and its receptor. Other findings of sex-specific molecular involvement in pain are subjected to pathway analyses and reveal at least one novel hypothesis: that females may preferentially use Th1 and males Th2 T cell activity to mediate chronic pain.
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Caracteres Sexuales , Animales , Humanos , Femenino , Masculino , Médula Espinal/fisiopatología , Médula Espinal/metabolismo , Dolor/fisiopatología , Dolor/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Hiperalgesia/fisiopatología , Microglía/metabolismo , Microglía/fisiología , Prolactina/metabolismoRESUMEN
SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.
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Antígenos Ly , Queratodermia Palmoplantar , Ratones Noqueados , Activador de Plasminógeno de Tipo Uroquinasa , Animales , Femenino , Masculino , Ratones , Antígenos Ly/genética , Antígenos Ly/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Ratones Endogámicos C57BL , Umbral del Dolor/fisiología , Activador de Plasminógeno de Tipo Uroquinasa/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.
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Dolor Crónico , Parvalbúminas , Parvalbúminas/metabolismo , Animales , Dolor Crónico/metabolismo , Dolor Crónico/fisiopatología , Ratones , Neuronas/metabolismo , Neuronas/fisiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Potenciales de Acción/fisiología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismoRESUMEN
Negative expectations can increase pain sensitivity, leading to nocebo hyperalgesia. However, the physiological and psychological factors that predispose individuals to this phenomenon are still not well understood. The present study examined whether stress induced by a social stressor affects nocebo hyperalgesia, and whether this effect is mediated by self-reported and physiological stress responses. We recruited 52 healthy participants (15 men) who were randomly assigned to either the Trier Social Stress Test (TSST) or a control condition (a friendly version of the TSST). Nocebo hyperalgesia was induced using negative suggestions combined with a validated pain conditioning paradigm. We assessed self-reported (anxiety and stress) and physiological (cortisol, alpha-amylase, heart rate, and skin conductance) responses to stress. Both groups exhibited significant nocebo hyperalgesia. The stress group showed higher levels of anxiety, self-reported stress, and cortisol levels compared to the control group while no significant differences were found in other physiological markers. The stress and control groups did not differ in the magnitude of nocebo hyperalgesia, but anxiety levels partially mediated the effects of the stress test on nocebo hyperalgesia. Our findings suggest that an external social stressor does not directly affect nocebo hyperalgesia, but that increased anxiety due to the stressor enhances its magnitude. Thus, it may be worthwhile to investigate whether reducing stress-related anxiety in clinical settings would help alleviate nocebo effects.
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Respuesta Galvánica de la Piel , Frecuencia Cardíaca , Hidrocortisona , Hiperalgesia , Efecto Nocebo , Autoinforme , Estrés Psicológico , Humanos , Masculino , Femenino , Hiperalgesia/fisiopatología , Hiperalgesia/psicología , Hidrocortisona/metabolismo , Hidrocortisona/análisis , Adulto Joven , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Respuesta Galvánica de la Piel/fisiología , Adulto , Frecuencia Cardíaca/fisiología , Ansiedad/fisiopatología , Ansiedad/psicología , Estrés Fisiológico/fisiología , Dimensión del Dolor , Saliva/metabolismo , Saliva/química , alfa-Amilasas/metabolismo , alfa-Amilasas/análisis , Umbral del Dolor/fisiología , Umbral del Dolor/psicologíaRESUMEN
BACKGROUND: The periaqueductal gray (PAG) plays a well-established pivotal role in the descending pain modulatory circuit. The objective of this study was to investigate morphological changes in the astroglia in models that are commonly used in pain and itch studies. METHODS: Five different mouse models of pain, as well as two models of chronic itch, were established using complete Freund's adjuvant (CFA), spared nerve injury (SNI), bone cancer pain (BCP), cisplatin (CIS), and paclitaxel (PTX) for pain, and diphenylcyclopropenone (DCP) and acetone and diethyl ether followed by water (AEW) for chronic itch. von Frey tests and video recordings were employed to assess pain and itching behaviors. The immunofluorescence of S100ß, pSTAT3, and glial fibrillary acidic protein (GFAP) was examined. Two- and three-dimensional studies were used to evaluate changes in astrocyte morphology. RESULTS: Significant scratching was caused by DCP and AEW, whereas the administration of CFA, SNI, BCP, CIS, and PTX produced clear mechanical allodynia. The expression of GFAP in the lPAG/vlPAG was upregulated in CFA, SNI, BCP, CIS, PTX, and DCP mice but decreased in AEW mice. According to Sholl analysis, CFA, SNI, PTX, and BCP mice showed substantially higher astrocyte intersections in the vlPAG, whereas CFA, SNI, BCP, CIS, and DCP mice presented longer peak lengths. In three-dimensional analysis, CFA, SNI, PTX, and DCP mice showed increased astrocyte surface areas, while CIS and AEW mice showed both reduced surface areas and/or volumes of astrocytes. CONCLUSION: The findings showed that different pain and itching conditions have different astrocyte morphologies, and these variations in morphological changes help to explain the pathophysiology of these conditions.