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)

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

The involvement of excitatory amino acid receptors in peripheral nociceptive processing was assessed in two separate experiments. In the first, one knee joint cavity of rats was injected with 0.1 ml of L-glutamate (0.001 mM; 0.1 mM; 1.0 mM), L-aspartate (0.001 mM; 0.1 mM: 1.0 mM), L-arginine (0.1 mM) or different combinations of these amino acids. The animals tested for paw withdrawal latency to radiant heat and withdrawal threshold to von Frey filaments at different time points. Combinations of glutamate/aspartate, aspartate/arginine or glutamate/aspartate/arginine when injected into the joint, in the absence of any other treatment, reduced the paw withdrawal latency and withdrawal threshold immediately after the injection and persisting up to 5 h indicating the development of hyperalgesia and allodynia. Subsequent intra-articular injection of either an NMDA or a non-NMDA glutamate receptor antagonist ((+/-)-2-amino-7-phosphonoheptanoic acid (AP7), 0.2 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 0.1 mM) attenuated the thermal hyperalgesia and the mechanical allodynia produced by glutamate/aspartate/arginine. On the other hand, in a second experiment intra-articular injection of AP7, ketamine or CNQX reversed the hyperalgesia and allodynia produced by injection of a mixture of kaolin and carrageenan into the joint. These receptor antagonists, however, did not have an effect on the joint edema. These findings provide evidence for a potential role of peripheral NMDA and non-NMDA receptors in nociceptive transmission.
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PMID:Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. 914 68

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

The endogenous opioid peptide dynorphin A has non-opioid effects that can damage the spinal cord when given in high doses. Dynorphin has been shown to increase the receptive field size of spinal cord neurons and facilitate C-fiber-evoked reflexes. Furthermore, endogenous dynorphin levels increase following damage to the spinal cord, injury to peripheral nerves, or inflammation. In this study, sensory processing was characterized following a single, intrathecal injection of dynorphin A (1-17) in mice. A single intrathecal injection of dynorphin A (1-17) (3 nmol, i.t.) induced mechanical allodynia (hind paw, von Frey filaments) lasting 70 days, tactile allodynia (paint brush applied to flank) lasting 14 days, and cold allodynia (acetone applied to the dorsal hind paw) lasting 7 days. Similarly, dynorphin A (2-17) (3 nmol, i.t.), a non-opioid peptide, induced cold and tactile allodynia analogous to that induced by dynorphin A (1-17), indicating the importance of non-opioid receptors. Pretreatment with the NMDA antagonists, MK-801 and LY235959, but not the opioid antagonist, naloxone, blocked the induction of allodynia. Post-treatment with MK-801 only transiently blocked the dynorphin-induced allodynia, suggesting the NMDA receptors may be involved in the maintenance of allodynia as well as its induction. We have induced a long-lasting state of allodynia and hyperalgesia by a single intrathecal injection of dynorphin A (1-17) in mice. The allodynia induced by dynorphin required NMDA receptors rather than opioid receptors. This result is consistent with results in rats and with signs of clinically observed neuropathic pain. This effect of exogenously administered dynorphin raises the possibility that increased levels of endogenous dynorphins associated with spinal cord injuries may participate in the genesis and maintenance of neuropathic pain.
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PMID:Spinally administered dynorphin A produces long-lasting allodynia: involvement of NMDA but not opioid receptors. 927 10

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

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

To investigate whether or not NMDA/nitric oxide (NO) pathways in the trigeminal system are involved in the development and/or maintenance of such pathological pain states as the hyperalgesia and allodynia observed after dental surgery, loose-ligation on the left inferior alveolar nerves of rats were performed. The responses to mechanical stimulation were then measured using von Frey filaments. Hypersensitivity to tactile stimulation developed on the ipsilateral side in ligated animals 5 days after surgery and lasted for at least 30 days. In addition, the effects of drugs on these pain states during the period 2-3 weeks following surgery were investigated. As a result, it was observed that tactile hypersensitivity was inhibited by the intraperitoneal (i.p.) administration of both MK-801 hydrogen maleate (0.05-0.1 mg/kg) and N(G)-monomethyl-L-arginine acetate (L-NMMA: 10-100 mg/kg). Still further, NO production and the number of neuronal NO synthase (nNOS)-positive neurons in the trigeminal nucleus caudalis (SpVc) was evaluated. As a result of these experiments, it was found that the changes in NO levels evoked by the intravenous infusions of N-methyl-D-aspartate (NMDA; 10 mg/kg) and MK-801 (0.5 mg/kg) were significantly larger in the loose-ligated rats compared to the sham-operated rats. Moreover, the number of nNOS-positive neurons was found to have increased on the ipsilateral side in layers I/II of the SpVc. These results would suggest that tactile hypersensitivity develops after inferior alveolar nerve injury and that NMDA receptor/NOS/NO production pathways in the SpVc may be involved in the development of such pathophysiological states.
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PMID:Involvement of NMDA-nitric oxide pathways in the development of tactile hypersensitivity evoked by the loose-ligation of inferior alveolar nerves in rats. 1256 Jan 29

Recent findings indicate that the spatial organization of the spinal nociceptive reflex system is adjusted postnatally through experience-dependent mechanisms. The cellular and molecular mechanisms underlying this tuning are not known. Because the adhesion molecule L1 is known to play an important role in neural development and synaptic plasticity, we studied the nociceptive withdrawal reflexes in awake adult mutant mice deficient in L1. Withdrawal reflexes were elicited by a CO(2) laser (heat stimulation) and von Frey monofilaments (tactile stimulation). L1-deficient mice (n=10) had an abnormally high nociceptive heat-reflex threshold compared with wild-type mice (n=11), except for the nose. Other behavioral signs of heat pain, such as vocalization, were either absent or strongly reduced in L1-deficient mice. Tactile thresholds for withdrawal reflexes were increased in L1-deficient mice when compared with wild-types except for the tail. By contrast, the spatial organization of the withdrawal reflexes appeared normal indicating that the L1 adhesion molecule is not essential for the spatial adjustments of reflex connections during development. The termination patterns of thin primary afferent fibers in the superficial dorsal horn, visualized using intra-plantar injections of WGA-HRP, were normal, suggesting that decreased nociceptive heat sensitivity in L1-deficient mice is mainly due to altered central processing. In view of the known interactions between L1 and some of the NMDA-receptor subtypes, and the prominent role of NMDA receptors in nociception and plasticity, it is conceivable that the hypoalgesia seen in L1 mutants is due, in part, to disturbed NMDA-receptor function.
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PMID:Heat nociception is severely reduced in a mutant mouse deficient for the L1 adhesion molecule. 1259 Nov 22

The CNS expresses many components of an extracellular protease signalling system, including the protease-activated receptor-1 (PAR-1) whose tethered ligand is generated by thrombin. Activation of PAR-1 potentiates NMDA receptor activity in hippocampal neurons. Because NMDA activity mediates hyperalgesia, we tested the hypothesis that PAR-1 receptors also regulate pain processing. In contrast to the potentiating effect of thrombin in the hippocampus, NMDA-induced behaviours and the transient mechanical hyperalgesia (von Frey fibres) induced by intrathecally injected NMDA in mice were inhibited by thrombin in a dose-related fashion. This anti-hyperalgesic effect was mimicked by SFLLRN, the natural ligand at PAR-1 binding sites, but not SLIGRL-amide, a PAR-2 agonist. The effects of SFLLRN were less potent and shorter in duration than that of thrombin, consistent with its more transient effect on PAR-1 sites. Both thrombin and SFLLRN inhibited acetic acid-induced abdominal stretch (writhing) behaviours, which were also sensitive to NMDA antagonism, but not hot plate or tail flick latencies, which were insensitive to NMDA antagonists. TFLLR-amide, a selective ligand for PAR-1 sites, mimicked the effects of thrombin while RLLFT-amide, an inactive, reverse peptide sequence, did not. In addition, the effect of TFLLR-amide was prevented by RWJ-56110, a PAR-1 antagonist. Thrombin and TFLLR-amide produced no oedema (Evans Blue extravasation) in the spinal cord that would account for these effects. Based on the reported ability of thrombin to mobilize endothelin-1 from astrocytes, we tested the role of this compound in thrombin's activity. BQ123, an endothelin A receptor antagonist, prevented thrombin's inhibition of writhing and NMDA-induced behaviours while BQ788, an endothelin B receptor antagonist, did not. Thus, activation of PAR-1 sites by thrombin in the CNS appears to inhibit NMDA-mediated nociception by a pathway involving endothelin type A receptors.
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PMID:Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: possible mediation by endothelin. 1271 3

The administration of kappa-opioid receptor antagonists, nor-binaltorphimine (norBNI) and 5'-guanidinonaltrindole (GNTI) enhanced allodynia in rats and mice after sciatic nerve ligation. In order to understand the mechanism underlying this effect, we examined the possible involvement of the endogenous ligand of kappa-opioid receptor dynorphin. The experiments were carried out on male Wistar rats and on Albino-Swiss mice. The rats had been implanted with a catheter 7 days earlier in the subarachnoid space of the spinal cord. Intrathecal (i.t.) administrations in mice were made by lumbar puncture. The animals were i.t. injected with norBNI, GNTI (kappa-opioid receptor antagonists), dynorphin A1-17 antiserum (DYN A/S), ketamine (NMDA receptor antagonist) and their combinations. The nociceptive sensitivity was assessed using the mechanical (von Frey) and thermal allodynia tests on days 2-4 and 8-10 after the sciatic nerve ligation. Both antagonists, norBNI and GNTI, significantly enhanced mechanical and thermal allodynia in rats and mice with neuropathic pain. The potentiation of allodynia after the administration of norBNI or GNTI was inhibited by earlier administration of DYN A/S or by ketamine. Our results suggest that allodynia is mediated through nonopioid effect of the endogenous opioid peptide, dynorphin. The nonopioid action is potentiated by the blockade of kappa-opioid receptors, and corresponding to the elevation of prodynorphin mRNA level in neuropathic pain. Furthermore, the potentiation of allodynia after the administration of the above drugs appears to be mediated through the activation of NMDA receptors directly by dynorphin.
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PMID:Antagonists of the kappa-opioid receptor enhance allodynia in rats and mice after sciatic nerve ligation. 1297 97


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