Articles: hyperalgesia.
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The effects of intrathecal (i.t.) administration of prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2) on behavioral and spinal neuronal responses to mechanical and thermal stimuli were examined in rats. i.t. Administration of either PGE2 (1-100 nmol) or PGF2 (1-100 nmol) produced a robust, dose-dependent mechanical hyperalgesia, but only a weak thermal hyperalgesia and touch-evoked allodynia. Spinal administration of either PGE2 (100 pmol-100 nmol) or PGF2 (1-100 nmol) produced dose-dependent increases in responses of nociceptive specific (NS) neurons to mechanical stimuli, but only modest increases in wide dynamic range (WDR) neurons to mechanical stimuli. ⋯ Both PGE2 and PGF2 produced increases in background discharges of WDR and NS neurons, although this effect was most consistently observed with WDR neurons and PGE2. These behavioral and electrophysiological data suggest that mechanical hyperalgesia induced by spinal administration of PGE2 and PGF2 is mediated mainly by changes in NS neurons. The weak thermal hyperalgesia may reflect changes in WDR neurons.
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Previous studies indicate that descending modulation of nociception is progressively increased following persistent inflammation. The present study was designed to further examine the role of supraspinal neurons in descending modulation following persistent inflammation. Constant levels of paw withdrawal (PW) and tail flick (TF) latencies to noxious heat stimuli were achieved in lightly anesthetized rats (pentobarbital sodium 3-10 mg/kg/h, i.v.). ⋯ Compared to vehicle-injected animals, microinjection of a soma-selective excitotoxin, ibotenic acid, enhanced ES-produced inhibition at 3 h but not at 24 h after inflammation. We propose that these time course changes reflect dynamic alterations in concomitant descending facilitation and inhibition. At early time points, NMDA receptor and NGC activation enhance descending facilitation; as time progresses, the dose-response curve of NMDA shifts to the left and descending inhibition dominates and masks any descending facilitation.
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Anesthesia and analgesia · May 2002
Selective and long-lasting neural blockade with resiniferatoxin prevents inflammatory pain hypersensitivity.
Capsaicin can produce a selective and long-lasting neural blockade. Resiniferatoxin (RTX) is an ultrapotent vanilloid agonist with a unique spectrum of activities different from that of capsaicin. We sought to determine whether a single application of RTX to a peripheral nerve could completely prevent the long-lasting mechanical hyperalgesia caused by carrageenan injection. In rat experiments, RTX (0.001%) was administered percutaneously to the sciatic and saphenous nerves before the intraplantar injection of carrageenan. Responses to noxious mechanical (pressure on the paw) and thermal (hot plate) stimulations and changes in paw circumference were measured at various time intervals for 8 days after treatment. The administration of RTX resulted in mechanical and thermal hypoalgesia (for 2 and 8 days, respectively). Inflammatory hyperalgesia was completely prevented by the precarrageenan injection of RTX. Inflammatory enhancement of paw circumference was reduced by RTX (12.0 +/- 2.4 mm versus 6.9 +/- 3.4 mm, P < 0.005). We suggest that the selective nature of the effect of vanilloid agonists on nociception could provide an opportunity for prolonged neural blockade when early mobilization and/or preservation of protective sensation are required. ⋯ We report that an ultrapotent vanilloid agonist resiniferatoxin can provide a selective and long-lasting neural blockade. Applied to the sciatic and saphenous nerves, it completely prevented pain hypersensitivity caused by prolonged inflammatory process (injection of carrageenan into the paw).
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Anesthesia and analgesia · May 2002
The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance.
Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. ⋯ Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.
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Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). ⋯ When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.