Articles: hyperalgesia.
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Growth hormone (GH) and GH-related signaling molecules play an important role in nociception and development of chronic pain. This review aims to examine the potential molecular mechanisms through which GH-related signaling modulates sensory hypersensitivity in rodents, the clinical pharmacology of GH, and the clinical evidence of GH treatment for several common pain syndromes. ⋯ Dysfunction of the GH/insulin-like growth factor 1 (IGF-1)/ghrelin axis was linked to hyperalgesia and several common clinical pain syndromes. Low levels of GH and IGF-1 were linked to pain hypersensitivity, whereas ghrelin appeared to provide analgesic effects. Pretreatment of GH reversed mechanical and thermal hypersensitivity in an animal model of inflammatory pain. Clinical trials support GH treatment in a subgroup of patients with fibromyalgia syndrome (level of evidence: 1B+) or chronic lower back pain syndrome (level of evidence: 2C+).
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Randomized Controlled Trial
The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects.
Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. ⋯ Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.
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Emerging evidence has indicated that colony-stimulating factor-1 (CSF1) modulates neuroinflammation in the central nervous system and the development of neuropathic pain, while the underlying mechanism remains unknown. Here, we identified the increased expression of CSF1 derived from activated astrocytes in the ipsilateral dorsal horn in rats with spinal nerve ligation (SNL). Suppression of CSF1 expression alleviated neuroinflammation, neuronal hyperexcitability, and glutamatergic receptor subunit upregulation in the dorsal horn and improved SNL-induced pain behavior. ⋯ Furthermore, SNL induced the expression of DNA methyltransferase 3a (DNMT3a) that was associated with the hypermethylation of the miR-214-3p promoter, leading to reduced miR-214-3p expression in the model rodents. Treatment with the DNMT inhibitor zebularine significantly reduced cytosine methylation in the miR-214-3p promoter; this reduced methylation consequently increased the expression of miR-214-3p and decreased the content of CSF1 in the ipsilateral dorsal horn and, further, attenuated IL-6 production and pain behavior in rats with SNL. Together, our data indicate that the DNMT3a-mediated epigenetic suppression of miR-214-3p enhanced CSF1 production in astrocytes, which subsequently induced neuroinflammation and pain behavior in SNL model rats.
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A significant subset of patients with urologic chronic pelvic pain syndrome suffer from widespread, as well as pelvic, pain and experience mood-related disorders, including anxiety, depression, and panic disorder. Stress is a commonly reported trigger for symptom onset and exacerbation within these patients. The link between stress and pain is believed to arise, in part, from the hypothalamic-pituitary-adrenal axis, which regulates the response to stress and can influence the perception of pain. ⋯ Serum corticosterone was significantly increased at 1 day after foot shock, and bladder mast cell degranulation rates were similarly high in both sham- and shock-exposed mice. Bladder cytokine and growth factor mRNA levels indicated a persistent shift toward a proinflammatory environment after foot shock exposure. Together, these data suggest that chronic stress exposure in an anxiety-prone mouse strain may provide a useful translational model for understanding mechanisms that contribute to widespreadness of pain and increased comorbidity in a subset of patients with urologic chronic pelvic pain syndrome.
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Clinical Trial
Allodynography: Reliability of a New Procedure for Objective Clinical Examination of Static Mechanical Allodynia.
There is a need for reliable and valid clinical assessment tools for quantifying allodynia in neuropathic pain. Allodynography has been proposed as a useful standardized procedure for clinical assessment of mechanical allodynia. This study (www.clinicaltrials.gov NCT02070367) undertook preliminary investigation of the measurement properties of allodynography, a new standardized clinical examination procedure for mapping the area of cutaneous allodynia. ⋯ This preliminary study supports the inter-rater and test-retest reliability of allodynography. Studies on larger samples in multiple contexts and reporting other measurement properties are warranted.