Articles: hyperalgesia.
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J. Pharmacol. Exp. Ther. · Jul 2001
Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS).
Although transcutaneous electrical nerve stimulation (TENS) is used extensively in inflammatory joint conditions such as arthritis, the underlying mechanisms are unclear. This study aims to demonstrate an opiate-mediated activation of descending inhibitory pathways from the rostral ventral medulla (RVM) in the antihyperalgesia produced by low- (4 Hz) or high-frequency (100 Hz) TENS. Paw withdrawal latency to radiant heat, as an index of secondary hyperalgesia, was recorded before and after knee joint inflammation (induced by intra-articular injection of 3% kaolin and carrageenan) and after TENS/no TENS coadministered with naloxone (20 microg/1 microl), naltrindole (5 microg/1 microl), or vehicle (1 microl) microinjected into the RVM. ⋯ The analgesia produced by DAMGO and deltorphin is selectively blocked by naloxone (p < 0.05) and naltrindole (p < 0.05), respectively. Thus, the dose of naloxone and naltrindole used in the current study blocks mu- and delta-opioid receptors, respectively. Hence, low-frequency and high-frequency TENS produces antihyperalgesia by activation of mu- and delta-opioid receptors, respectively, in the RVM.
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The effects of a p38 stress-activated protein kinase inhibitor, 4-(4-fluorophenyl)-2-(-4-methylsulfonylphenyl)-5-(4-pyridynyl) imidazole (SB203580), were evaluated in a rat model of inflammatory hyperalgesia. Oral, but not intrathecal, administration of SB203580 significantly reversed inflammatory mechanical hyperalgesia induced by injection of complete Freund's adjuvant into the hindpaw. SB203580 did not, however, affect the increased levels of interleukin-1beta and cyclo-oxygenase 2 protein observed in the hindpaw following complete Freund's adjuvant injection. ⋯ In addition, following interleukin-1beta injection into the ipsilateral paw, co-administration of SB203580 with des-Arg(9)-bradykinin into the contralateral paw inhibited the bradykinin B(1) receptor-mediated hyperalgesia. In human embryonic kidney 293 cells expressing the human bradykinin B(1) receptor, its agonist des-Arg(10)-kallidin produced a rapid phosphorylation of endogenous p38 stress-activated protein kinase. Our data suggest that p38 stress-activated protein kinase is involved in the development of inflammatory hyperalgesia in the rat, and that its pro-inflammatory effects involve the induction of the bradykinin B(1) receptor as well as functioning as its downstream effector.
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The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. ⋯ This effect was prevented by co-administration of the CB(1) receptor antagonist SR141716a, but not by co-administration of the CB(2) receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB(1) receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone. These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB(1) receptor.
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The generation of transgenic mice that lack or overexpress genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is widely used in mice. Here we describe a novel model, chemical stimulation of the colon, which we have developed in mice. ⋯ The peak behavioural responses were evoked by 0.1% capsaicin and by 1% mustard oil respectively. The nociceptive behavioural responses were dose-dependently reversed by morphine (ED50 = 1.9 +/- 1 mg/kg s.c.). We conclude that this model represents a useful tool both for phenotyping mutant mice and for classical pharmacology since information on visceral pain, referred hyperalgesia and colon inflammation can all obtained from the same animal.
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J. Peripher. Nerv. Syst. · Jun 2001
Etanercept reduces hyperalgesia in experimental painful neuropathy.
Etanercept, a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein competitively inhibits tumor necrosis factor-alpha (TNF). Etanercept has been successfully used in patients with rheumatoid arthritis, where it reduces pain and inflammation. Because locally produced proinflammatory cytokines play a role in pain after nerve injury, we investigated whether etanercept can reduce pain and hyperalgesia in an animal model of painful neuropathy, the chronic constriction injury of the sciatic nerve. ⋯ Treatment with etanercept reduced thermal hyperalgesia and mechanical allodynia significantly in both modes of application. The effect of etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hyperalgesia was already present. These results suggest the potential of etanercept as a treatment option for patients with neuropathic pain.