RESUMO
Pain is the main complication of sickle cell disease (SCD). Individuals with SCD experience acute pain episodes and chronic daily pain, both of which are managed with opioids. Opioids have deleterious side effects and use-associated stigma that make them less than ideal for SCD pain management. After recognizing the neuropathic qualities of SCD pain, clinically-approved therapies for neuropathic pain, including gabapentin, now present unique non-opioid based therapies for SCD pain management. These experiments explored the efficacy of gabapentin in relieving evoked and spontaneous chronic pain, and hypoxia/reoxygenation (H/R)-induced acute pain in mouse models of SCD. When administered following H/R, a single dose of gabapentin alleviated mechanical hypersensitivity in SCD mice by decreasing peripheral fibre activity. Gabapentin treatment also alleviated spontaneous ongoing pain in SCD mice. Longitudinal daily administration of gabapentin failed to alleviate H/R-induced pain or chronic evoked mechanical, cold or deep tissue hypersensitivity in SCD mice. Consistent with this observation, voltage-gated calcium channel (VGCC) α2 δ1 subunit expression was similar in sciatic nerve, dorsal root ganglia and lumbar spinal cord tissue from SCD and control mice. Based on these data, gabapentin may be an effective opioid alternative for the treatment of chronic spontaneous and acute H/R pain in SCD.
Assuntos
Anemia Falciforme , Dor Crônica , Gabapentina/farmacologia , Hiperalgesia , Hipóxia , Nervo Isquiático , Doença Aguda , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Animais , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Dor Crônica/metabolismo , Dor Crônica/patologia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Camundongos , Camundongos Transgênicos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologiaRESUMO
Approximately one-third of individuals with sickle cell disease (SCD) develop chronic pain. This debilitating pain is inadequately treated because the underlying mechanisms driving the pain are poorly understood. In addition to persistent pain, patients with SCD are also in a tonically proinflammatory state. Previous studies have revealed that there are elevated plasma levels of many inflammatory mediators including chemokine (c-c motif) ligand 2 (CCL2) in individuals with SCD. Using a transgenic mouse model of SCD, we investigated the contributions of CCL2 signaling to SCD-related pain. Inhibition of chemokine receptor 2 (CCR2), but not CCR4, alleviated the behavioral mechanical and cold hypersensitivity in SCD. Furthermore, acute CCR2 blockade reversed both the behavioral and the in vitro responsiveness of sensory neurons to an agonist of TRPV1, a neuronal ion channel previously implicated in SCD pain. These results provide insight into the immune-mediated regulation of hypersensitivity in SCD and could inform future development of analgesics or therapeutic measures to prevent chronic pain.