Articles: hyperalgesia.
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Poor quality sleep is a common complaint among people with chronic pain. The co-occurrence of poor sleep quality and chronic pain often comes with increased pain intensity, more disability and a higher cost of healthcare. Poor sleep has been suggested to affect measures of peripheral and central pain mechanisms. To date, sleep provocations are the only models proven to affect measures of central pain mechanisms in healthy subjects. However, there are limited studies investigating the effect of several nights of sleep disruption on measures of central pain mechanisms. ⋯ Poor quality of sleep is often experienced by patients with chronic pain, with the most common complaint being nightly awakenings. This exploratory study is the first to investigate changes in measures of central and peripheral pain sensitivity in healthy subjects after sleep disruptions for three consecutive nights without any restrictions on total sleep time. The findings suggest that disruptions to sleep continuity in healthy individuals can induce increased sensitivity to measures of central and peripheral pain sensitization.
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Chronic pain is a significant health problem associated with disability and reduced quality of life. Current management of chronic pain is inadequate with only modest effects of pharmacological interventions. Thus, there is a need for the generation of analgesics for treating chronic pain. ⋯ Sustained release of SARM, from the microparticle formulation, was observed both in vitro and in vivo for 4 weeks. Selective androgen receptor modulator treatment produced no cardiac or liver toxicity and did not produce rewarding behaviors. These studies demonstrate that SARM-loaded microparticles, which release drug for a sustained period, alleviate muscle pain, are safe, and may serve as a potential therapeutic for chronic muscle pain.
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Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain.
Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A-blocked VEGF-A-mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. ⋯ In rats with spared nerve injury-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain.
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Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. ⋯ Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.
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Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. ⋯ We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.