The journal of pain : official journal of the American Pain Society
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Chronic pain is extremely difficult to manage, in part due to lack of progress in reversing the underlying pathophysiology. Since translation of messenger ribonucleic acids (mRNAs) in the peripheral terminal of the nociceptor plays a role in the transition from acute to chronic pain, we tested the hypothesis that transient inhibition of translation in the peripheral terminal of the nociceptor could reverse hyperalgesic priming, a model of transition from acute to chronic pain. We report that injection of translation inhibitors rapamycin and cordycepin, which inhibit translation by different mechanisms, at the peripheral terminal of the primed nociceptor produces reversal of priming in the rat that outlasted the duration of action of these drugs to prevent the development of priming. These data support the suggestion that interruption of translation in the nociceptor can reverse a preclinical model of at least 1 form of chronic pain. ⋯ This study provides evidence that ongoing protein translation in the sensory neuron terminals is involved in pain chronification, and local treatment that transiently interrupts this translation may be a useful therapy to chronic pain.
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This study investigated putative mechanisms of impaired spinal opioid antinociception such as a downregulation of mu-opioid receptor (MOR) number, coupling, and efficacy in rats with advanced (12 weeks) streptozotocin (STZ)-induced diabetes. Intravenous injection of STZ (45 mg/kg) in Wistar rats led to selective degeneration of insulin-producing pancreatic ß-cells, elevated blood glucose, and mechanical hyperalgesia. In these animals, dose-dependent and naloxone-reversible intrathecal fentanyl antinociception was significantly impaired and associated with a loss in MOR immunoreactivity of calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerve terminals, membrane-bound MOR binding sites, and MOR-stimulated G protein coupling within the dorsal horn of the spinal cord. Intrathecal delivery of nerve growth factor (NGF) in diabetic animals normalized spinal MOR number and G protein coupling and rescued spinal fentanyl-induced antinociception. These findings identify for the first time a loss in functional MOR on central terminals of sensory neurons as a contributing factor for the impaired spinal opioid responsiveness during advanced STZ-induced diabetes that can be reversed by NGF. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (eg, arthritis, cancer, neuropathy) and may give novel therapeutic incentives. ⋯ In diabetic neuropathy a loss in sensory neuron mu-opioid receptor number and coupling contributes to impaired spinal opioid antinociception that can be reversed by NGF. These findings support growing evidence of a distinct regulation of opioid responsiveness during various painful diseases and may give novel therapeutic incentives.
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Review Meta Analysis
Structural brain anomalies and chronic pain: a quantitative meta-analysis of gray matter volume.
The diversity of chronic pain syndromes and the methods employed to study them make integrating experimental findings challenging. This study performed coordinate-based meta-analyses using voxel-based morphometry imaging results to examine gray matter volume (GMV) differences between chronic pain patients and healthy controls. There were 12 clusters where GMV was decreased in patients compared with controls, including many regions thought to be part of the "pain matrix" of regions involved in pain perception, but also including many other regions that are not commonly regarded as pain-processing areas. The right hippocampus and parahippocampal gyrus were the only regions noted to have increased GMV in patients. Functional characterizations were implemented using the BrainMap database to determine which behavioral domains were significantly represented in these regions. The most common behavioral domains associated with these regions were cognitive, affective, and perceptual domains. Because many of these regions are not classically connected with pain and because there was such significance in functionality outside of perception, it is proposed that many of these regions are related to the constellation of comorbidities of chronic pain, such as fatigue and cognitive and emotional impairments. Further research into the mechanisms of GMV changes could provide a perspective on these findings. ⋯ Quantitative meta-analyses revealed structural differences between brains of individuals with chronic pain and healthy controls. These differences may be related to comorbidities of chronic pain.
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This study examined the factor structure of the Children's Depression Inventory (CDI) among children and adolescents with chronic pain using exploratory and confirmatory factor analysis in a large, multisite sample of treatment-seeking youth. Participants included 1,043 children and adolescents (ages 8-18) with a range of chronic pain complaints who presented for initial evaluation at 1 of 3 tertiary care pediatric chronic pain clinics across the United States. They completed the CDI and reported on pain intensity and functional disability. Factor analysis was conducted using a 2-step (exploratory and confirmatory) approach. Results supported a 5-factor model for the CDI with good fit to the data. The distribution and item-total correlations of the somatic items (eg, pain complaints, fatigue) were explored in this sample. Results indicate that the CDI is a useful tool for assessing depressive symptoms in youth with chronic pain, but some caution is warranted in interpreting the clinical significance of scores in light of the overlap of specific symptoms common to both pain and depression. ⋯ The CDI can be considered a valid tool for assessing mood symptoms in children with chronic pain. Caution is encouraged when interpreting the clinical significance of scores due to symptom overlap between chronic pain and depression.
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An inverse association between resting blood pressure (BP) and acute pain sensitivity is well documented. Whether BP-related hypoalgesia differs by gender is unclear from prior work. Whether it increases proportionally with BP throughout the full BP range is also unknown. We examined BP-related hypoalgesia in a general population sample (n = 10,371, aged 30-87) of equal gender distribution reflecting the extremely low through hypertensive BP range. Resting BP was assessed and individuals participated in a standardized cold pressor test, providing pain ratings every 9 seconds. For systolic BP (SBP), a significant SBP × Gender interaction was observed on mean pain ratings (P < .001). Females displayed significant BP-related hypoalgesia (P < .001), with males showing a 38% smaller effect (P < .001). A similar DBP × Gender interaction was also observed (P < .05). Spline regression indicated a significant (P < .001) change in slope of the SBP-pain association at 140 mmHg. Among individuals with lower resting SBP (<140/90), increasing hypoalgesia with increasing SBP levels was observed (P < .001), with no further increases in those with higher BP (≥140/90; P > .10). This is the first large-scale study to confirm past results suggesting that BP-related hypoalgesia differs by gender; that is, females exhibited greater hypoalgesia. BP-related hypoalgesia appears subject to ceiling effects in the hypertensive BP range. ⋯ Females show greater BP-related hypoalgesia than males, highlighting gender differences in endogenous antinociceptive systems. Extent of BP-related hypoalgesia does not increase further once resting pressures reach the hypertensive range, suggesting persistent maximal demands on these antinociceptive systems among hypertensive individuals.