Role of the sigma-1 receptor in the pathophysiology of osteoarthritis pain
Osteoarthritis is the most common musculoskeletal disease worldwide, characterized by degradation of the articular cartilage, chronic joint pain and disability. Currently available treatments for osteoarthritis have limited efficacy and significant side effects. Understanding the neurobiological mec...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/668154 |
| Acceso en línea: | http://hdl.handle.net/10803/668154 |
| Access Level: | acceso abierto |
| Palabra clave: | Osteoarthrits pain Sigma-1 receptor Analgesi Opioid tolerance Central sensitization Dolor osteoartrític Receptor sigma-1 Analgèsia Tolerància opioide Sensibilització central 616.7 |
| Sumario: | Osteoarthritis is the most common musculoskeletal disease worldwide, characterized by degradation of the articular cartilage, chronic joint pain and disability. Currently available treatments for osteoarthritis have limited efficacy and significant side effects. Understanding the neurobiological mechanisms involved in the development and maintenance of this chronic pain condition and the pain-related comorbidities is crucial to develop novel therapeutic alternatives. The present thesis is focused on the role of the sigma-1 receptor (σ1R), a chaperone expressed in key areas for pain control, modulating chronic osteoarthritis pain and opioid analgesic tolerance. Using a mouse model of osteoarthritis pain, we demonstrated that the pharmacological blockade of the σ1R produces acute and long-lasting effects inhibiting osteoarthritis pain and its cognitive and emotional manifestations. Moreover, the σ1R antagonist restored morphine-induced antinociception in opioid-tolerant individuals, constituting a potential therapeutic strategy for the multimodal management of chronic pain. We found that the σ1R antagonist modulates a neurobiological pathway common to osteoarthritis pain and opioid tolerance, involving µ-opioid receptor activity, neuroinflammation and glutamatergic signalling. The relevance of this pathway is highlighted through the identification of a promising treatment, based on simultaneous blockade of σ1R and stimulation of the µ-opioid receptor, which relieves osteoarthritis pain without inducing tolerance. Overall we combined behavioural, biochemical and electrophysiological approaches to advance in the understanding of the role of σ1R on osteoarthritis pain manifestations, and identified σ1R antagonists as efficient therapeutic agents to inhibit chronic osteoarthritis pain and the deleterious side effects of opioid prescription drugs. |
|---|