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1.
Physiol Rev ; 101(1): 213-258, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32525759

RESUMEN

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.


Asunto(s)
Dolor Agudo/fisiopatología , Encéfalo/fisiopatología , Dolor Crónico/fisiopatología , Red Nerviosa/fisiopatología , Animales , Humanos , Vías Nerviosas , Neurotransmisores , Transducción de Señal/fisiología
2.
Nature ; 606(7912): 137-145, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35614217

RESUMEN

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.


Asunto(s)
Hiperalgesia , Neuralgia , Nociceptores , Piel , Animales , Dolor Crónico/fisiopatología , Hiperalgesia/fisiopatología , Mecanorreceptores/patología , Ratones , Neuralgia/fisiopatología , Nociceptores/patología , Piel/inervación , Piel/fisiopatología
3.
Proc Natl Acad Sci U S A ; 121(27): e2403777121, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38916998

RESUMEN

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.


Asunto(s)
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/metabolismo
4.
Physiol Rev ; 99(2): 1079-1151, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30672368

RESUMEN

Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.


Asunto(s)
Dolor Crónico/metabolismo , Umbral del Dolor , Células Receptoras Sensoriales/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Analgésicos/uso terapéutico , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Dolor Crónico/fisiopatología , Diseño de Fármacos , Humanos , Umbral del Dolor/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Transducción de Señal , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Canales de Sodio Activados por Voltaje/efectos de los fármacos , Canales de Sodio Activados por Voltaje/genética
5.
Gastroenterology ; 166(6): 976-994, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38325759

RESUMEN

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.


Asunto(s)
Dolor Crónico , Dolor Visceral , Humanos , Dolor Visceral/fisiopatología , Dolor Visceral/terapia , Dolor Visceral/diagnóstico , Dolor Visceral/etiología , Dolor Crónico/terapia , Dolor Crónico/fisiopatología , Dolor Crónico/diagnóstico , Dolor Crónico/psicología , Animales , Calidad de Vida , Transducción de Señal
6.
Nat Rev Neurosci ; 21(9): 485-498, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32699292

RESUMEN

Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere in the nervous system. SGCs in sensory ganglia are activated by numerous types of nerve injury and inflammation. The activation includes upregulation of glial fibrillary acidic protein, stronger gap junction-mediated SGC-SGC and neuron-SGC coupling, increased sensitivity to ATP, downregulation of Kir4.1 potassium channels and increased cytokine synthesis and release. There is evidence that these changes in SGCs contribute to chronic pain by augmenting neuronal activity and that these changes are consistent in various rodent pain models and likely also in human pain. Therefore, understanding these changes and the resulting abnormal interactions of SGCs with sensory neurons could provide a mechanistic approach that might be exploited therapeutically in alleviation and prevention of pain. We describe how SGCs are altered in rodent models of four common types of pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic pain and post-herpetic pain.


Asunto(s)
Dolor Crónico/fisiopatología , Ganglios Autónomos/fisiopatología , Ganglios Sensoriales/fisiopatología , Células Satélites Perineuronales/fisiología , Animales , Humanos
7.
Nature ; 565(7737): 86-90, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30532001

RESUMEN

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.


Asunto(s)
Adaptación Psicológica/fisiología , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Vías Nerviosas/fisiología , Animales , Reacción de Prevención , Condicionamiento Clásico , Femenino , Humanos , Masculino , Núcleo Talámico Mediodorsal/citología , Núcleo Talámico Mediodorsal/fisiología , Ratones , Neuronas Aferentes/fisiología , Núcleos Parabraquiales/citología , Núcleos Parabraquiales/fisiología , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Canales Catiónicos TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
8.
Neuroimage ; 297: 120711, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38942099

RESUMEN

The ability to perceive pain presents an interesting evolutionary advantage to adapt to an ever-changing environment. However, in the case of chronic pain (CP), pain perception hinders the capacity of the system to adapt to changing sensory environments. Similar to other chronic perceptual disorders, CP is also proposed to be a maladaptive compensation to aberrant sensory predictive processing. The local-global oddball paradigm relies on learning hierarchical rules and processing environmental irregularities at a local and global level. Prediction errors (PE) between actual and predicted input typically trigger an update of the forward model to limit the probability of encountering future PEs. It has been hypothesised that CP hinders forward model updating, reflected in increased local deviance and decreased global deviance. In the present study, we used the local-global paradigm to examine how CP influences hierarchical learning relative to healthy controls. As hypothesised, we observed that deviance in the stimulus characteristics evoked heightened local deviance and decreased global deviance of the stimulus-driven PE. This is also accompanied by respective changes in theta phase locking that is correlated with the subjective pain perception. Changes in the global deviant in the stimulus-driven-PE could also be explained by dampened attention-related responses. Changing the context of the auditory stimulus did not however show a difference in the context-driven PE. These findings suggest that CP is accompanied by maladaptive forward model updating where the constant presence of pain perception disrupts local deviance in non-nociceptive domains. Furthermore, we hypothesise that the auditory-processing based biomarker identified here could be a marker of domain-general dysfunction that could be confirmed by future research.


Asunto(s)
Dolor Crónico , Humanos , Masculino , Femenino , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Adulto , Adulto Joven , Percepción del Dolor/fisiología , Electroencefalografía , Adaptación Fisiológica/fisiología , Percepción Auditiva/fisiología , Atención/fisiología
9.
J Neurochem ; 168(11): 3617-3619, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38991093

RESUMEN

This preface introduces the Journal of Neurochemistry Special Issue on pain research. While acute pain provides important sensory information, which aids in the protection of an organism, it can in some cases transition into a chronic state. Unfortunately, chronic pain is a highly disabling state characterised by intense and abnormal pain sensations, which are exacerbated by problematic psychosocial disturbances that are poorly treated by current drugs. This issue includes several reviews that address current issues spanning basic to clinical research on a range of pain syndromes. Also included is a collection of basic research articles investigating important aspects of pain signalling through to whole body aspects of pain integration.


Asunto(s)
Dolor , Humanos , Animales , Dolor/psicología , Dolor/fisiopatología , Dolor Crónico/psicología , Dolor Crónico/fisiopatología
10.
Hum Brain Mapp ; 45(10): e26780, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38984446

RESUMEN

Past cross-sectional chronic pain studies have revealed aberrant resting-state brain activity in regions involved in pain processing and affect regulation. However, there is a paucity of longitudinal research examining links of resting-state activity and pain resilience with changes in chronic pain outcomes over time. In this prospective study, we assessed the status of baseline (T1) resting-state brain activity as a biomarker of later impairment from chronic pain and a mediator of the relation between pain resilience and impairment at follow-up. One hundred forty-two adults with chronic musculoskeletal pain completed a T1 assessment comprising a resting-state functional magnetic resonance imaging scan based on regional homogeneity (ReHo) and self-report measures of demographics, pain characteristics, psychological status, pain resilience, pain severity, and pain impairment. Subsequently, pain impairment was reassessed at a 6-month follow-up (T2). Hierarchical multiple regression and mediation analyses assessed relations of T1 ReHo and pain resilience scores with changes in pain impairment. Higher T1 ReHo values in the right caudate nucleus were associated with increased pain impairment at T2, after controlling for all other statistically significant self-report measures. ReHo also partially mediated associations of T1 pain resilience dimensions with T2 pain impairment. T1 right caudate nucleus ReHo emerged as a possible biomarker of later impairment from chronic musculoskeletal pain and a neural mechanism that may help to explain why pain resilience is related to lower levels of later chronic pain impairment. Findings provide empirical foundations for prospective extensions that assess the status of ReHo activity and self-reported pain resilience as markers for later impairment from chronic pain and targets for interventions to reduce impairment. PRACTITIONER POINTS: Resting-state markers of impairment: Higher baseline (T1) regional homogeneity (ReHo) values, localized in the right caudate nucleus, were associated with exacerbations in impairment from chronic musculoskeletal pain at a 6-month follow-up, independent of T1 demographics, pain experiences, and psychological factors. Mediating role of ReHo values: ReHo values in the right caudate nucleus also mediated the relationship between baseline pain resilience levels and later pain impairment among participants. Therapeutic implications: Findings provide empirical foundations for research extensions that evaluate (1) the use of resting-state activity in assessment to identify people at risk for later impairment from pain and (2) changes in resting-state activity as biomarkers for the efficacy of treatments designed to improve resilience and reduce impairment among those in need.


Asunto(s)
Dolor Crónico , Imagen por Resonancia Magnética , Descanso , Humanos , Masculino , Femenino , Dolor Crónico/fisiopatología , Dolor Crónico/diagnóstico por imagen , Adulto , Persona de Mediana Edad , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Dolor Musculoesquelético/fisiopatología , Dolor Musculoesquelético/diagnóstico por imagen , Resiliencia Psicológica , Estudios Prospectivos , Biomarcadores , Estudios Longitudinales , Estudios de Seguimiento
11.
J Pharmacol Exp Ther ; 389(3): 268-276, 2024 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-38702195

RESUMEN

The prefrontal cortex (PFC) has justifiably become a significant focus of chronic pain research. Collectively, decades of rodent and human research have provided strong rationale for studying the dysfunction of the PFC as a contributing factor in the development and persistence of chronic pain and as a key supraspinal mechanism for pain-induced comorbidities such as anxiety, depression, and cognitive decline. Chronic pain alters the structure, chemistry, and connectivity of PFC in both humans and rodents. In this review, we broadly summarize the complexities of reported changes within both rodent and human PFC caused by pain and offer insight into potential pharmacological and nonpharmacological approaches for targeting PFC to treat chronic pain and pain-associated comorbidities. SIGNIFICANCE STATEMENT: Chronic pain is a significant unresolved medical problem causing detrimental changes to physiological, psychological, and behavioral aspects of life. Drawbacks of currently approved pain therapeutics include incomplete efficacy and potential for abuse producing a critical need for novel approaches to treat pain and comorbid disorders. This review provides insight into how manipulation of prefrontal cortex circuits could address this unmet need of more efficacious and safer pain therapeutics.


Asunto(s)
Corteza Prefrontal , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/metabolismo , Humanos , Animales , Dolor Crónico/fisiopatología , Dolor Crónico/terapia , Dolor/fisiopatología , Dolor/tratamiento farmacológico
12.
J Urol ; 211(3): 341-353, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38109700

RESUMEN

PURPOSE: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research. MATERIALS AND METHODS: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals. RESULTS: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms. CONCLUSIONS: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.


Asunto(s)
Cistitis Intersticial , Dolor Pélvico , Prostatitis , Humanos , Cistitis Intersticial/terapia , Cistitis Intersticial/fisiopatología , Dolor Pélvico/etiología , Dolor Pélvico/terapia , Dolor Pélvico/diagnóstico , Dolor Pélvico/fisiopatología , Prostatitis/complicaciones , Prostatitis/terapia , Brote de los Síntomas , Dolor Crónico/terapia , Dolor Crónico/etiología , Dolor Crónico/diagnóstico , Dolor Crónico/fisiopatología , Masculino , Calidad de Vida
13.
Osteoarthritis Cartilage ; 32(8): 982-989, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38763431

RESUMEN

OBJECTIVE: Individuals with chronic pain due to knee osteoarthritis (OA) are insufficiently physically active, and alterations of facilitatory and inhibitory nociceptive signaling are common in this population. Our objective was to examine the association of these alterations in nociceptive signaling with objective accelerometer-based measures of physical activity in a large observational cohort. DESIGN: We used data from the Multicenter Osteoarthritis Study. Measures of peripheral and central pain sensitivity included pressure pain threshold at the knee and mechanical temporal summation at the wrist, respectively. The presence of descending pain inhibition was assessed by conditioned pain modulation (CPM). Physical activity was quantitatively assessed over 7 days using a lower back-worn activity monitor. Summary metrics included steps/day, activity intensity, and sedentary time. Linear regression analyses were used to evaluate the association of pain sensitivity and the presence of descending pain inhibition with physical activity measures. RESULTS: Data from 1873 participants was analyzed (55.9% female, age = 62.8 ± 10.0 years). People having greater peripheral and central sensitivity showed lower step counts. CPM was not significantly related to any of the physical activity measures, and none of the exposures were significantly related to sedentary time. CONCLUSIONS: In this cohort, greater peripheral and central sensitivity were associated with reduced levels of objectively-assessed daily step counts. Further research may investigate ways to modify or treat heightened pain sensitivity as a means to increase physical activity in older adults with knee OA.


Asunto(s)
Ejercicio Físico , Osteoartritis de la Rodilla , Umbral del Dolor , Humanos , Femenino , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/fisiopatología , Osteoartritis de la Rodilla/complicaciones , Anciano , Umbral del Dolor/fisiología , Ejercicio Físico/fisiología , Dimensión del Dolor , Dolor Crónico/fisiopatología , Acelerometría , Artralgia/fisiopatología
14.
Stress ; 27(1): 2402954, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-39320055

RESUMEN

Chronic pain is a prevalent condition with significant impacts on individuals' lives, including heightened stress and impaired physiological functioning. Given that work and family are the two main social domains where stress manifests, this study aimed to investigate the interactions between chronic pain, work-family stressors, and diurnal cortisol patterns to understand how chronic pain affects daily life and physiological stress responses. We identified 1,413 adults with chronic pain and 1,413 matched controls within MIDUS II samples to examine work-family spillover, daily work and home stressors, and cortisol levels across multiple days. The chronic pain group reported more negative work to family spillover and experienced more instances of stressful home events, particularly avoided arguments. These results align with literature suggesting chronic pain exacerbates tensions in close relationships and increases stress. The chronic pain group also had higher cortisol levels cross late-day periods, indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is associated with poorer health outcomes, including increased inflammation and psychological distress. We did not find any differences in previously identified cortisol profiles, which are higher-level summaries of cortisol levels within each day. We discuss why such difference might not have appeared in this sample.


Asunto(s)
Dolor Crónico , Ritmo Circadiano , Hidrocortisona , Saliva , Estrés Psicológico , Humanos , Hidrocortisona/metabolismo , Masculino , Femenino , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Persona de Mediana Edad , Ritmo Circadiano/fisiología , Estrés Psicológico/fisiopatología , Adulto , Saliva/química , Saliva/metabolismo , Familia , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología
15.
PLoS Biol ; 19(3): e3001154, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33739978

RESUMEN

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1ß production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.


Asunto(s)
Dolor Crónico/etiología , Microglía/fisiología , Nervios Espinales/metabolismo , Animales , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Channelrhodopsins/metabolismo , Dolor Crónico/fisiopatología , Femenino , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Microglía/metabolismo , Optogenética/métodos , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Nervios Espinales/fisiología
16.
J Neural Transm (Vienna) ; 131(5): 563-580, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38570361

RESUMEN

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse. However, the causal effect between chronic pain and the development of SUDs has not been clearly established. In this review, we discuss evidence that affirms the proposition that chronic pain is a risk factor for the development of opioid and cannabis use disorders by outlining the clinical evidence and detailing neurobiological mechanisms that link pain and drug misuse. Central to the link between chronic pain and opioid and cannabis misuse is hypodopaminergic transmission and the modulation of dopamine signaling in the mesolimbic pathway by opioids and cannabis. Moreover, we discuss the role of kappa opioid receptor activation and neuroinflammation in the context of dopamine transmission, their contribution to opioid and cannabis withdrawal, along with potential new treatments.


Asunto(s)
Analgésicos Opioides , Dolor Crónico , Trastornos Relacionados con Opioides , Humanos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Analgésicos Opioides/efectos adversos , Animales , Abuso de Marihuana/complicaciones , Abuso de Marihuana/fisiopatología
17.
Neuroendocrinology ; 114(10): 894-906, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38801814

RESUMEN

BACKGROUND: Multiple factors, including neurobiological, hormonal, psychological, and social/cultural norms, influence the manner in which individuals experience pain. Adipose tissue, once considered solely an energy storage site, has been recognized as a significant endocrine organ that produces and releases a range of hormones and cytokines. In recent years, research has highlighted the role of adipose tissue and its endocrine factors in the pathophysiology of pain. SUMMARY: This narrative review aimed to provide a comprehensive overview of the current knowledge on the endocrine aspects of pain pathophysiology, with a specific focus on adipose tissue. We examine the role of adipokines released by adipose tissue, such as leptin, adiponectin, resistin, visfatin, asprosin in pain perception and response. We also explore the clinical implications of these findings, including the potential for personalized pain management based on endocrine factors and adipose tissue. KEY MESSAGES: Overall, given this background, this review intended to highlight the importance of understanding the endocrine aspects of pain pathophysiology, particularly focusing on the role of adipose tissue, in the development of chronic pain and adipokines. Better understanding the role of adipokines in pain modulation might have therapeutic implications by providing novel targets for addressing underlying mechanism rather than directly focusing on symptoms for chronic pain, particularly in obese individuals.


Asunto(s)
Adipoquinas , Tejido Adiposo , Humanos , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Adipoquinas/metabolismo , Adipoquinas/fisiología , Dolor/fisiopatología , Dolor/metabolismo , Animales , Dolor Crónico/fisiopatología , Dolor Crónico/metabolismo
18.
Expert Opin Emerg Drugs ; 29(2): 155-164, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38602142

RESUMEN

INTRODUCTION: Chronic lower back pain is a leading cause of disability and healthcare spending worldwide. Discogenic pain, pain originating from the intervertebral disk, is a common etiology of chronic lower back pain. Currently, accepted treatments for chronic discogenic pain focus only on the management of symptoms, such as pain. There are no approved treatments that stop or reverse degenerating intervertebral discs. Biologic therapies promoting disc regeneration have been developed to expand treatment options. VIADISC™ NP, is a viable disc allograft supplementation that, in a recent trial, demonstrated a significant reduction in pain and increased function in patients suffering from symptomatic degenerative disc disease. AREAS COVERED: This manuscript summarizes the epidemiology and etiology of low back pain, the pathophysiology of degenerative disc disease, current treatments, and a need for newer therapies. The rationale behind intradiscal biologics for the treatment of symptomatic degenerative disc disease is also discussed. EXPERT OPINION: Characterization of the biology leading to disc degeneration has allowed for the development of intradiscal biologics. They may soon be capable of preventing and reversing disc degeneration. Clinical trials have shown promise, but further research into efficacy and safety is needed before these therapies are widely employed.


Asunto(s)
Dolor Crónico , Degeneración del Disco Intervertebral , Dolor de la Región Lumbar , Humanos , Degeneración del Disco Intervertebral/fisiopatología , Dolor de la Región Lumbar/etiología , Dolor de la Región Lumbar/fisiopatología , Dolor de la Región Lumbar/tratamiento farmacológico , Dolor de la Región Lumbar/terapia , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Dolor Crónico/etiología , Animales , Disco Intervertebral/fisiopatología , Disco Intervertebral/patología , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Productos Biológicos/administración & dosificación , Desarrollo de Medicamentos
19.
Clin Exp Rheumatol ; 42(6): 1187-1197, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38607679

RESUMEN

OBJECTIVES: Central sensitivity (CS) is defined as an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold inputs. CS has recently been linked to the psychological burden associated with chronic pain, such as fibromyalgia (FM). The primary objective of this study is to investigate the impact of specific psychological constructs on CS in patients with FM. In Study 1, we explore the influence of temperament, personality, childhood trauma, defence mechanisms, and mental pain on CS. In Study 2, our goal is to test the role of the best predictors of CS in influencing quality of life (QoL) and FM functioning through a path analysis model. METHODS: A total of 510 women with FM participated online, completing a self-administered protocol. Data collection took place between April and June of 2023. RESULTS: In Study 1, higher levels of low sensory threshold (ß=0.210), traumatic experiences of physical threat (ß=0.141), neurotic defences (ß=0.124), and mental pain (ß=0.241) emerged as the strongest predictors of increased CS. In Study 2, the presented model demonstrated a satisfactory fit (chi2=27.200; df=10; p=0.002; GFI=0.984; NFI=0.949; CFI=0.967; RMSEA=0.061 [95% CI 0.034-0.090]) with large and medium effect sizes on physical (-0.576) and psychological (-0.190) QoL. CONCLUSIONS: The study underscores the pivotal role of psychological dimensions in influencing CS levels and their relationships with QoL in patients with FM.


Asunto(s)
Fibromialgia , Calidad de Vida , Humanos , Fibromialgia/psicología , Fibromialgia/fisiopatología , Fibromialgia/diagnóstico , Femenino , Persona de Mediana Edad , Adulto , Sensibilización del Sistema Nervioso Central , Modelos Psicológicos , Umbral del Dolor/psicología , Personalidad , Temperamento , Dolor Crónico/psicología , Dolor Crónico/fisiopatología , Dolor Crónico/diagnóstico
20.
Clin Exp Rheumatol ; 42(6): 1224-1229, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38966941

RESUMEN

OBJECTIVES: Fibromyalgia (FM) is characterised by chronic widespread pain, often associated with fatigue, sleep disturbance, cognitive and mood impairment. Pain is a complex and multidimensional experience that significantly impacts personal, social, and professional functioning. Psychological factors related to chronic pain include catastrophising and self-efficacy in managing the painful condition. Therefore, this study explores the influence of chronic pain and related psychological factors on functional outcomes in FM patients. METHODS: In this study, 91 Italian patients with FM were assessed using an online questionnaire. The questionnaire included instruments to assess pain, such as the Numerical Rating Scale (NRS) and the Brief Pain Inventory (BPI), psychological characteristics, such as the Pain Self-Efficacy Questionnaire (PSEQ) and the Pain Catastrophizing Scale (PCS), and health-related quality of life with the 12-item Short Form Survey (SF-12). Multiple regression models were run, using the Interference subscale of the BPI and the physical and mental components of the SF-12 as outcomes, and the NRS, PCS and PSEQ scales as predictors. RESULTS: Our analysis revealed that in our model, both PCS and PSEQ were significant predictors of BPI-Interference (PCS: ß=0.29; p=0.001; PSEQ: ß=-0.36; p<0.001); NRS and PSEQ significantly predicted SF-12-Physical score (NRS: ß=-0.32; p=<0.001; PSEQ: ß=.50; p<0.001); PCS was found to be the only significant predictor of SF-12-Mental scores (ß=-0.53; p<0.001). CONCLUSIONS: Our results suggested that psychological variables such as catastrophic thinking and self-efficacy play a significant role in determining daily functioning and physical and mental health status in FM patients, showing greater influence than pain intensity.


Asunto(s)
Catastrofización , Dolor Crónico , Fibromialgia , Estado Funcional , Dimensión del Dolor , Calidad de Vida , Autoeficacia , Humanos , Fibromialgia/psicología , Fibromialgia/fisiopatología , Fibromialgia/diagnóstico , Femenino , Persona de Mediana Edad , Masculino , Dolor Crónico/psicología , Dolor Crónico/fisiopatología , Dolor Crónico/diagnóstico , Adulto , Catastrofización/psicología , Encuestas y Cuestionarios , Italia , Anciano , Costo de Enfermedad
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