Pain
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The role of peroxynitrite (PN) as a mediator of nociceptive signaling is emerging. We recently reported that the development of central sensitization that follows the intraplantar injection of carrageenan in rats is associated with spinal PN synthesis. We now demonstrate that a significant pathway through which spinal PN modulates central sensitization is post-translational tyrosine nitration of key proteins involved in the glutamatergic pathway, namely glutamate transporter GLT-1 and glutamine synthetase (GS). ⋯ Carrageenan-induced hyperalgesia was also associated with nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) known to provide a critical source of PN during central sensitization. Nitration of GLT-1 and GS contributes to central sensitization by enhancing glutamatergic neurotransmission. Our results support the critical role of nitroxidative stress in the development of hyperalgesia and suggest that post-translational nitration of enzymes and transporters linked to glutamatergic neurotransmission represent a novel mechanism of central sensitization.
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Randomized Controlled Trial
Low-dose amitriptyline for treatment of persistent arm pain due to repetitive use.
Amitriptyline is sometimes used to treat arm pain related to repetitive use, but rigorous evidence of its benefit is lacking. This randomized controlled trial investigated whether amitriptyline provided greater pain relief or improved arm function than a placebo pill in adults with arm pain associated with repetitive use that had persisted for at least 3 months. Participants (N=118) were randomly assigned to receive 25mg of amitriptyline or a placebo pill for 6 weeks. ⋯ The most frequent side effect was drowsiness. In conclusion, this study found that low-dose amitriptyline did not significantly decrease arm pain among these participants but did significantly improve arm function and well being. Future research is needed to explore the effects of higher doses and longer duration of treatment.
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Back pain severity has extensively been targeted in clinical and epidemiologic studies. However, despite the importance of a valid pain severity grading its adequate conceptualization in the general population has received comparatively little attention. The potentially misleading influence of measurement error remains unclear. ⋯ This classification showed statistically significant and clinically important associations to health-related variables. Our results confirm the high burden of back pain in the general population but suggest a different categorization of those with severe back pain. This entails consequences on how to best target this important health problem from a public health perspective.
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Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. ⋯ Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.
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Randomized Controlled Trial
A randomized placebo-controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain.
A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography. ⋯ The patients in MB injection group showed a mean reduction in pain measured by NRS of 52.50, a mean reduction in Oswestry disability scores of 35.58, and satisfaction rates of 91.6%, compared with 0.70%, 1.68%, and 14.3%, respectively, in placebo treatment group (p<0.001, p<0.001, and p<0.001, respectively). No adverse effects or complications were found in the group of patients treated with intradiscal MB injection. The current clinical trial indicates that the injection of methylene blue into the painful disc is a safe, effective and minimally invasive method for the treatment of intractable and incapacitating discogenic low back pain.