Articles: hyperalgesia.
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We used functional MRI and a longitudinal design to investigate the brain mechanisms in a previously reported estrogen-dependent visceral hypersensitivity model. We hypothesized that noxious visceral stimulation would be associated with activation of the insula, anterior cingulate cortex, and amygdala, and that estrogen-dependent, stress-induced visceral hypersensitivity would both enhance activation of these regions and recruit activation of other brain areas mediating affect and reward processing. Ovariectomized rats were treated with estrogen (17 β-estradiol, E2) or vehicle (n = 5 per group) and scanned in a 7T MRI at three different time points: pre-stress (baseline), 2 days post-stress, and 18 days post-stress. ⋯ This unexpected finding suggests that E2 may dramatically alter visceral nociceptive processing in the brain following an acute stressor. This study is the first to examine estrogen-stress dependent interactions in response to noxious visceral stimulation using functional MRI. Future studies that include other control groups and larger sample sizes are needed to fully understand the interactions between sex hormones, stress, and noxious stimulation on brain activity.
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This study investigated mesencephalic dopamine depletion effects on static mechanical allodynia (SMA) elicited by chronic constriction of the infraorbitary nerve (CCI-IoN). ⋯ This study demonstrates that nigrostriatal dopamine depletion exacerbates the neuropathic pain resulting from CCI-IoN. This effect is probably due to an action through descending pain inhibitory systems which increased pain sensitization at the MDH level. It demonstrates also an analgesic effect elicited by D2R activation at the segmental level.
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Increasing evidence suggests that microRNAs are functionally involved in the initiation and maintenance of pain hypersensitivity, including chronic morphine analgesic tolerance, through the posttranscriptional regulation of pain-related genes. We have previously demonstrated that miR-219 regulates inflammatory pain in the spinal cord by targeting calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ). However, whether miR-219 regulates CaMKIIγ expression in the dorsal root ganglia to mediate morphine tolerance remains unclear. ⋯ These results demonstrate that miR-219 contributes to the development of chronic tolerance to morphine analgesia in mouse dorsal root ganglia by targeting CaMKIIγ and enhancing CaMKIIγ-dependent brain-derived neurotrophic factor expression.
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Obesity and chronic pain are often comorbid and their rates are increasing. It is unknown whether increased pain is caused by greater weight or poor diet quality or both. Therefore, we utilized a Total Western Diet (TWD) to investigate the functional and physiologic consequences of nutritionally poor diet in mice. For 13 weeks on the commercially available TWD, based on the National Health and Nutrition Examination Survey, thresholds of TWD-fed mice significantly increased in both thermal and mechanical tests. Quantitative magnetic resonance imaging revealed a significant increase in fat mass with a concomitant decrease in lean mass in the TWD-fed mice. In addition, there were significant increases in levels of serum leptin and inflammatory cytokines. After chronic pain induction using complete Freund's adjuvant, hypersensitivity was more pronounced and significantly prolonged in the TWD-fed mice. Therefore, prolonged exposure to poor diet quality resulted in altered acute nociceptive sensitivity, systemic inflammation, and persistent pain after inflammatory pain induction. ⋯ These results highlight the negative effects of poor diet quality with respect to recovery from hypersensitivity and susceptibility to chronic pain. A complete understanding of the impact of diet can aid in treatment and recovery dynamics in human clinical patients.
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The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC90 of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. ⋯ In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC90 concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms.