Articles: hyperalgesia.
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Many patients with irritable bowel syndrome (IBS) have lowered sensory thresholds to rectal distention when compared to control subjects, a phenomenon called visceral hypersensitivity. ⋯ Our results do not support the usefulness of the electronic rectal barostat as a diagnostic method to diagnose IBS.
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The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1-30mg/kg, i.p.), a balanced serotonergic-noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3-100mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03-10mg/kg, i.p.) and desipramine (1-30mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. ⋯ In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or SSRI-NRI combinations, produces synergistic analgesic efficacy.
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J. Pharmacol. Exp. Ther. · Dec 2006
Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity.
Prostaglandin E(2) (PGE(2)) is both an inflammatory mediator released at the site of tissue inflammation and a neuromodulator that alters neuronal excitability and synaptic processing. The effects of PGE(2) are mediated by four G-protein-coupled EP receptors (EP1-EP4). ⋯ AH23848 also reduces the PGE(2)-mediated sensitization of capsaicin-evoked currents in DRG neurons in vitro. These data suggest that EP4 is a potential target for the pharmacological treatment of inflammatory pain.
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Although mechanical hyperalgesia associated with medical procedures is the major source of severe pain in burn-injured patients, little is known about its underlying mechanism. One reason for this has been the lack of a model for mechanical hyperalgesia at the site of injury. We have modified an established partial-thickness burn model in the rat to produce long-lasting primary mechanical hyperalgesia, which is present from the first measurement at 0.5 h, reaches a maximum at 3 days, and is still significant after 7 days. Because nerve growth factor (NGF), which is elevated in burn-injured tissue, produces mechanical hyperalgesia and activates protein kinase C (PKC)-epsilon, a key mediator in inflammatory and neuropathic pain, we used this model to evaluate the role of the NGF receptor, tyrosine-receptor kinase A (TrkA), and PKC-epsilon in burn-induced primary mechanical hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides to TrkA and PKC-epsilon, starting 3 days before inducing a burn injury, caused dose-related decrease of burn-induced primary mechanical hyperalgesia. In addition, intradermal injection of a PKC-epsilon-selective inhibitor eliminated hyperalgesia. Our model provides a method to elucidate the underlying mechanism of burn-injury pain as well as to screen for targets for novel analgesic treatments of this important clinical condition. ⋯ This manuscript presents the first model of thermal injury-induced mechanical hyperalgesia which mimics prolonged duration of clinical burn injury pain. We also perform proof of concept experiments demonstrating that our model provides a method to elucidate the mechanism of this important clinical condition.
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Recent data support an important role for calcitonin gene-related peptide (CGRP) in deep tissue nociceptive processing. Using real-time reverse transcriptase polymerase chain reaction (RT-PCR), radioimmunoassay, immunohistochemistry and behavioral testing, we studied the early time course of CGRP mRNA and protein expression as well as nociceptive behavior following muscle inflammation. A rapid and significant increase in CGRP mRNA occurred in the mandibular division (V3) of the ipsilateral trigeminal ganglion at 30 minutes, 4 and 24 h after the injection of complete Freund's adjuvant as an inflammatory agent into rat masseter muscle. ⋯ Behavioral testing showed a reduction in head withdrawal thresholds bilaterally from 30 min through 24 h following muscle inflammation. Thus upregulation of CGRP mRNA and iCGRP levels are temporally related to the development of inflammation and lowered pain thresholds. The present data support the hypothesis that CGRP is upregulated during deep tissue inflammation and suggest that gene transcription is involved in this upregulation.