Articles: hyperalgesia.
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Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg. kg(-1). day(-1) for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg. kg(-1). day(-1) for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds. ⋯ The chronic administration of opioids followed by abrupt cessation can lead to a state of hyperalgesia. In these studies we demonstrate that the hyperalgesia from opioid cessation and from hind paw incision are additive in rats. We suggest that failure to take into consideration preoperative opioid use can lead to excessive postoperative pain.
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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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Chronic-constriction injury (CCI) of the sciatic nerve causes mechanical and heat hyperalgesia and mechanical allodynia in the plantar surface of the hindpaw. The underlying mechanism thought to account for these phenomena include central sensitization induced by peripheral nerve injury, ie, the increase in neuronal activity of spinal dorsal horn neurons. As a marker of neuronal activation of the central nervous system, Fos expression has been used widely to monitor the change in neuronal activity evoked by peripheral input. ⋯ The number of noxious stimulus-evoked Fos-labeled neurons in both the superficial and deep laminae of the dorsal horn in the CCI rats was increased significantly compared with those in sham-operated rats, suggesting an increased excitability of dorsal horn neurons to noxious stimuli. Concurrent EA treatment to the Zusanli point with the pinch stimulus suppressed the increase in the number of Fos-labeled cells in the spinal dorsal horn in the CCI rats. The present results show that EA treatment has antinociceptive effects on both pain behavior and neuronal activation of the spinal dorsal horn neurons in CCI rats.
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Randomized Controlled Trial Clinical Trial
'Balanced analgesia' in the perioperative period: is there a place for ketamine?
We investigated whether intraoperative 'subanesthetic doses' of ketamine have a postoperative anti-hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. ⋯ These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route.
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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.