Articles: hyperalgesia.
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Fibromyalgia is a prevalent and burdensome disorder characterized by chronic widespread pain and complex comorbid symptoms. To develop better treatments for pain-centered fibromyalgia symptoms, there is still a need for animal models which mimic the features of fibromyalgia patients. In the present study, we have established a fibromyalgia animal model by utilizing a never-before-published pharmacological effect of reserpine. ⋯ Pregabalin, duloxetine, and pramipexole significantly attenuated the reserpine-induced decrease in muscle pressure threshold, but diclofenac did not. The validity of the use of this reserpinized animal as a fibromyalgia model is demonstrated from three different aspects, i.e., face validity (manifestation of chronic pain and comorbid symptoms), construct validity (dysfunction of biogenic amine-mediated central nervous system pain control is involved), and predictive validity (similar responses to treatments used in fibromyalgia patients). This animal model is expected to contribute to the better understanding of fibromyalgia pathophysiology and the evaluation of drugs, especially those which would activate biogenic amine system.
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Neurogastroenterol. Motil. · Nov 2009
5-HT 3 receptors mediate the time-dependent vagal afferent modulation of nociception during chronic food allergen-sensitized visceral hyperalgesia in rats.
Converging lines of evidence demonstrate a vagally mediated antinociceptive pathway in animals undergoing acute visceral insults, the contribution of this system to visceral pain following chronic noxious stimuli is unknown. 5-HT(3) receptor (5-HT(3)Rs) on spinal afferents are crucially involved in nociceptive processing, the role of 5-HT(3)Rs on vagal afferents is unclear. The aim of the present study was to determine the contribution of vagal afferents to visceral nociception in rats undergoing chronic luminal allergen stimulation and whether it involves vagal 5-HT(3)Rs. Sensitized rats received chicken egg albumin (EA, 1 mg mL(-1)) in drinking water for 2 weeks (day 1-14). ⋯ Intraluminal infusion of a 5-HT(3)R antagonist (granisetron), whether alone or infused after local mucosa anaesthetic with 1% lidocaine, mimicked the effects of vagotomy. The mRNA levels for 5-HT(3B) or 5-HT(3A) subunit in the NG showed an opposite time-course to that of visceral pain, which increased from day 2, then decreased gradually to levels lower than those of controls. Our results demonstrate a time-dependent vagal afferent modulation of chronic allergen-sensitized visceral hyperalgesia, which may involve a 5-HT(3)R pathway.
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Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir(2.1)) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir(2.1)). Expression of hKir(2.1) in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. ⋯ In the formalin test, rats transduced with hKir(2.1) showed enhanced nocifensive behaviors (both Phase I and II, p < 0.05, n = 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir(2.1) before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of approximately 150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.
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Neuroscience letters · Oct 2009
Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice.
Although mu-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used mu-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking mu, delta, and kappa opioid receptors. ⋯ MK-801 blocked and reversed hyperalgesia caused by the acute injection and continuous infusion of fentanyl, respectively, in naltrexone-treated CD-1 mice, indicating the contribution of NMDA receptors to fentanyl hyperalgesia. These data show that the synthetic opioid fentanyl causes hyperalgesia independently of prior or concurrent opioid receptor activity or analgesia. Since the biotransformation of fentanyl does not yield any known pronociceptive metabolites, these data challenge assumptions regarding the role of neuroexcitatory metabolites in opioid-induced hyperalgesia.