Pain
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Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET(A)) and endothelin B (ET(B)) receptors, and is secreted in high concentrations in many different cancer environments. Although ET(A) receptor activation has an established nociceptive effect in cancer models, the role of ET(B) receptors on cancer pain is controversial. EDNRB, the gene encoding the ET(B) receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. ⋯ ET(B) mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET(B) receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.
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Acid-sensing ion channels (ASICs) are activated by acidic pH and may play a significant role in the development of hyperalgesia. Earlier studies show ASIC3 is important for induction of hyperalgesia after muscle insult using ASIC3-/- mice. ASIC3-/- mice lack ASIC3 throughout the body, and the distribution and composition of ASICs could be different from wild-type mice. ⋯ ASIC3 mRNA in DRG and protein levels in muscle were decreased in vivo by miR-ASIC3. In CHO-K1 cells co-transfected with ASIC1a and ASIC3, miR-ASIC3 reduced the amplitude of acidic pH-evoked currents, suggesting an overall inhibition in the surface expression of heteromeric ASIC3-containing channels. Our results show, for the first time, that reducing ASIC3 in vivo in primary afferent fibers innervating muscle prevents the development of inflammatory hyperalgesia in wild-type mice, and thus, may have applications in the treatment of musculoskeletal pain in humans.
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Review Meta Analysis Comparative Study
Comparing patients' and clinician-researchers' outcome choice for psychological treatment of chronic pain.
In pain treatment, outcomes are generally defined by researchers and clinicians, predominantly using patient self-report. A large-scale survey of people with chronic pain found a more extensive range of treatment outcomes rated important (Turk et al., "Identifying important outcome domains for chronic pain clinical trials: an IMMPACT survey of people with pain." PAIN 2008;137:276-85) than are conventionally used (Turk et al., "Core outcome domains for chronic pain clinical trials: IMMPACT recommendations." PAIN 2003;106:337-45). We compared outcomes from 60 randomised, controlled trials of cognitive and/or behavioural treatment for persistent pain with the 19 domains rated as most important in the survey. ⋯ Five of the 19 outcomes important to survey respondents were not measured at all, and 8 rarely. There was a positive, although modest, correlation between the methodological quality of trials and their coverage of survey respondents' outcomes. We lack measures in many areas of outcome valued by people with chronic pain, and we need to extend routine measurement of trial outcomes.