Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162473 (Frey)
 2,599 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve ligation injury in rats may represent a useful model of some clinical neuropathic pains. Activation of N-methyl-D-aspartate (NMDA) receptors may maintain central sensitivity and contribute to neuropathic pain. Here, nerve injury was produced by unilateral ligation of the L5 and L6 spinal roots of the sciatic nerve of rats. Catheters were inserted for intrathecal (i.th.) or local delivery of drugs at the site of nerve ligation. Acute nociception was measured by the 55 degrees C water tail flick test in sham-operated and nerve-injured rats, and allodynia was determined by measuring response to von Frey filaments. In sham-operated rats, morphine (30 micrograms, i.th.) produced a 60 +/- 14.4% MPE (maximal possible effect). MK-801 pretreatment did not alter tail-flick latency or morphine antinociception in sham-operated rats. In nerve-injured rats, morphine (30 micrograms, i.th.) produced a significantly lower antinociceptive effect than in controls (34 +/- 6.3% MPE). While MK-801 alone did not alter tail-flick latency in nerve-injured rats, it significantly enhanced the antinociceptive effect of morphine to 84 +/- 16.0% MPE. Bupivacaine (0.2 ml, 0.75% w/v) at the site of injury also significantly increased the efficacy of morphine (100 +/- 0% MPE) without affecting tail flick latency alone. Bupivacaine administered at the site of injury also produced a significant antiallodynic effect of 94 +/- 7.4% MPE. The reduction in antinociceptive efficacy of i.th. morphine in nerve injured rats may be due, in part, to an ongoing spontaneous activity initiated by ectopic foci at the site of injury, and possible NMDA receptor-mediated activity of spinal neurons.
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PMID:The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive. 858 50

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
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PMID:Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone. 912 15

Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain ('wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1 degree burn injury covering 12.5 cm2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a 'wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia ('wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the 'wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and 'wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect 'wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.
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PMID:Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. 927 93

1. Rats develop tactile allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2. Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether tactile allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3. Dose-dependent inhibition of tactile allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the alpha2-adrenoceptor agonist dexmedetomidine, the mu-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4. No effect on tactile allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5. These data suggest that the tactile allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.
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PMID:Spinal pharmacology of tactile allodynia in diabetic rats. 942 Dec 98

Evidence indicates that excitatory amino acids (EAAs) like glutamate and aspartate are important in the processing of nociceptive information in the dorsal horn of the spinal cord. Recently, the role of particular EAA receptors in pain transmission and facilitated pain states has been examined utilizing spinal administration of specific receptor antagonists. Most investigators have studied the involvement of N-methyl-D-aspartate (NMDA) EAA receptors in hyperalgesia and nociception; less is known about the importance of non-NMDA EAA receptors in animal models of persistent pain. To study the role of spinal non-NMDA EAA receptors in pain behaviors caused by an incision, we examined the effect of i.t. administered non-NMDA EAA receptor antagonists in a rat model of postoperative pain. Rats with i.t. catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound using von Frey filaments, response frequency to application of a non-punctate stimulus applied directly to the wound and non-evoked pain behaviors were measured before and after administration of i.t. 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), or vehicle. A separate group of animals were also tested for motor impairment caused by these drugs. In the vehicle-treated group, the median withdrawal threshold for punctate hyperalgesia decreased from 522 mN before surgery to 39 mN 2 h later; hyperalgesia was persistent. Intrathecal administration of 5 or 10 nmol of NBQX returned the withdrawal threshold toward preincision values; the median withdrawal thresholds were 158 and 360 mN, respectively. Intrathecal administration of 10 nmol of DNQX similarly increased the withdrawal threshold after incision. In separate groups of animals, i.t. administration of 5 or 10 nmol of NBQX decreased the response frequency to a non-punctate stimulus applied directly to the incision from 100+/-0% 2 h after surgery to 22+/-11 and 0+/-0% 30 min after drug injection, respectively. Similar results were observed with i.t. administration of 10 nmol of DNQX. Intrathecal NBQX also inhibited non-evoked pain behavior. In conclusion, non-NMDA receptor antagonists produced a marked decrease in pain behaviors in this model of postoperative pain. Thus, non-NMDA receptors are important for the maintenance of short-term pain behaviors caused by an incision and drugs blocking these receptors may be useful for the treatment of postoperative pain in patients.
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PMID:Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. 952 Feb 36

Histamine elicits the sensation of itch at the site of skin application as well as alloknesis (itch elicited by innocuous mechanical stimuli) in a surrounding area in humans and expansion of the low-threshold mechanosensitive receptive field area of spinal wide dynamic range (WDR)-type dorsal horn neurons in rats. We presently tested if the histamine-evoked expansion of neuronal receptive field area depends on a spinal N-methyl-D-aspartate (NMDA) receptor-mediated process. In pentobarbital sodium-anesthetized rats, mechanical receptive field areas of single WDR-type dorsal horn neurons were mapped with graded von Frey filaments before and 10 min after intracutaneous (ic) microinjection of histamine (1 microl; 1, 3, or 10%) at a low-threshold site within the receptive field. Intracutaneous microinjection of histamine evoked dose-related increases in firing rate, as well as a dose-dependent expansion in mean receptive field area 10 min after 3 and 10%, but not 1%, histamine doses. When a noncompetitive or competitive NMDA receptor antagonist dizocilpine [MK-801; D(-)-2-amino-5-phosphonovalerate (APV), respectively; 1 microM] was first applied topically to the surface of the spinal cord, there was no significant change in mean receptive field area after ic microinjection of 10% histamine. The mean neuronal response to histamine in the presence of spinal MK-801 or APV was not significantly different from the mean response to histamine in the absence of these drugs. These results suggest that spinal NMDA receptors are involved in histamine-induced expansion of mechanical receptive field area, a neural event possibly involved in the development of alloknesis.
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PMID:Spinal NMDA receptor involvement in expansion of dorsal horn neuronal receptive field area produced by intracutaneous histamine. 953 32

We investigated the role of NMDA receptors in memory encoding and retrieval. A delayed matching-to-place (DMP) paradigm in the watermaze was used to examine 1-trial spatial memory in rats. Over periods of up to 21 days, 4 daily trials were given to an escape platform hidden in a new location each day, with the memory interval (ITI) varying from 15 sec to 2 hours between trials 1 and 2, but always at 15 sec for the remaining ITIs. Using chronic i.c.v. infusions of D-AP5, acute intrahippocampal infusions, ibotenate hippocampus + dentate lesions and relevant aCSF or sham surgery control groups, we established: (1) the DMP task is hippocampal-dependent; (2) D-AP5 causes a delay-dependent impairment of memory in which the Groups x Delay interaction was significant on two separate measures of performance; (3) this memory impairment also occurs with acute intrahippocampal infusions; (4) the impairment occurs irrespective of whether the animals stay in or are removed from the training context during the memory delay interval; and (5) D-AP5 affects neither the retrieval of information about the spatial layout of the environment, nor memory of where the escape platform had been located on the last day before the start of chronic D-AP5 infusion. LTP in vivo in the dentate gyrus was blocked in the chronically-infused D-AP5 rats and HPLC measurements at sacrifice revealed appropriate intrahippocampal levels. Acute intrahippocampal infusion of radiolabelled D-AP5 revealed relatively restricted diffusion and was used to estimate whole-tissue hippocampal drug concentrations. These results indicate that (1) short-term memory for spatial information is independent of NMDA receptors; (2) the rapid consolidation of spatial information into long-term memory requires activation of hippocampal NMDA receptors; (3) NMDA receptors are not involved in memory retrieval; and (4) the delay-related effects of NMDA receptor antagonists on performance of this task cannot be explained in terms of sensorimotor disturbances. The findings relate to the idea that hippocampal synaptic plasticity is involved in event-memory (Morris and Frey, Phil Trans R Soc Lond B 1997;352:1489-1503) and to a computational model of one-trial DMP performance of Foster et al. (unpublished data).
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PMID:Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. 1022 71

Cold-freeze injury at -4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)-4-methylglutamic acid (SYM-2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague-Dawley rats were evaluated for frequency of withdrawal from von Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to -4 degrees C for 15 min (n=24). For control rats (n=24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post-operative day, SYM-2081 (150 or 100 mg/kg), fentanyl citrate (0. 04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p<0.05). SYM-2081 and fentanyl significantly reduced these responses (p<0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.
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PMID:SYM-2081 a kainate receptor antagonist reduces allodynia and hyperalgesia in a freeze injury model of neuropathic pain. 1070 Jun 3

In a previous study, we found that subcutaneous (s.c.) intraplantar injection of bee venom unilaterally could produce bilateral heat hyperalgesia. However, the bee venom-induced heat hyperalgesia identified in the injection site was presumed to be different from that identified in the contralateral hindpaw, since the former co-existed with the mechanical hyperalgesia while the latter did not. The aim of the present study was to testify whether the contralateral heat hyperalgesia identified in the bee venom model was a consequence of central changes. The radiant heat and von Frey-type filaments were applied to both the injection site and the contralateral pawpad of conscious rats prior to and 4 h after s.c. bee venom injection. After confirmation of the development of primary heat and mechanical hyperalgesia and contralateral heat hyperalgesia following s.c. bee venom, the sciatic nerve of the injection side was transected. After axotomy, the bee venom-induced heat hyperalgesia in the non-injected hindpaw was not altered at all compared with that prior to axotomy. Moreover, intrathecal pre-treatment with either N-methyl-D-aspartate (NMDA) or non-NMDA receptor antagonist could prevent the development of the contralateral heat hyperalgesia. The present results suggest that central sensitization contributes to development of the bee venom-induced contralateral heat hyperalgesia and activation of both NMDA and non-NMDA receptors in the spinal cord is involved in the processing.
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PMID:Contralateral heat hyperalgesia induced by unilaterally intraplantar bee venom injection is produced by central changes: a behavioral study in the conscious rat. 1077 Nov 58

We examine the effect of morphine or ketamine (N-methyl-D-aspartate receptor antagonist; NMDA) treatment on secondary hyperalgesia. Drug treatment started preinjury and continued into the early postinjury period. Hyperalgesia was induced by a local 1 degrees burn injury covering 12.5 cm(2) on the medial side of the calf. In this double-blind, cross-over study, 12 healthy volunteers received, on 3 separate days and in randomized order: (1) placebo; (2) morphine, bolus 150 microg/kg + infusion 1 microg/kg per min and 0.5 microg/kg per min; and (3) ketamine, bolus 60 microg/kg + infusion 6 microg/kg per min and 3 microg/kg per min. Bolus + infusion started 30 min before injury and ended 50 min after it. The area of secondary hyperalgesia was quantitated using punctate (von Frey filaments) and brush stimuli (electric brush). On the day of placebo, all subjects developed an area of hyperalgesia to punctate and brush stimuli outside the thermal injury (secondary hyperalgesia). We show that ketamine or morphine treatment starting preinjury significantly reduces this development (P<0.01, both). In a previous study, we found that postinjury treatment alone with morphine did not affect secondary hyperalgesia, whereas ketamine did so significantly. The differential response to morphine administered pre- or postinjury may be relevant to the recently shown NMDA receptor mediated interaction of central hyperexcitability and morphine antinociception. The effect of ketamine supports the hypothesis of the role of NMDA receptor mediation in central hyperexcitability.
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PMID:Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man. 1081 59


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