Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl-D-aspartate (NMDA) antagonists in guinea-pigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg/kg SC) and (-)NANM (1 and 10 mg/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity, whereas the sigma ligand pentazocine induced sedation but no flattened posture. Ketamine (20 mg/kg SC) and (+)dizocilpine (0.025, 0.1 and 1 mg/kg SC) produced similar effects to those of (+) and (-)NANM. However, the putative sigma receptor ligand DTG (1 and 10 mg/kg SC) had no observable effect on behaviours in guinea-pigs, similar to results for other species. The behavioural effects produced by (+) and (-)NANM were not reversed by injection 1 h later of naloxone hydrochloride (15 mg/kg SC), haloperidol (10 mg/kg SC) or DTG (10 and 30 mg/kg SC), but the effects of all drugs were reversed by the selective dopamine D-2 agonist quinpirole (3 mg/kg IP). Moreover, injection of naloxone (15 mg/kg SC), DTG (10 and 30 mg/kg SC) or haloperidol (1 and 10 mg/kg SC) 10 min before, did not reverse the behaviour induced by (+)NANM (10 mg/kg SC). These data indicate that sigma and PCP-like drugs have a similar gross behavioural effect in guinea-pigs, possibly mediated by non-competitive antagonism of the NMDA subtype of glutamate receptors. The results demonstrating behavioural depression were in contrast to the stimulatory effects of these drugs at similar doses in other rodent species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs. 168 18

Ketamine and MK-801 are phencyclidine (PCP)-like noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor that produce a use-dependent blockade of the NMDA receptor-coupled channel. Recent studies have suggested that the binding properties of these drugs to the NMDA receptor in-vitro are different. In the present study, the effects of ketamine and MK-801 on the induction of long-term potentiation (LTP) were compared at perforant path--granule cell synapses in anaesthetized rats. LTP was observed in animals treated with either saline or MK-801, but not in those treated with ketamine. These results reveal that ketamine and MK-801 differentially modulate the induction of LTP, and we propose that this differential modulation may be related to the different binding properties of the drugs.
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PMID:Differential effects of ketamine and MK-801 on the induction of long-term potentiation. 183 85

Both chiral forms of ketamine caused analgesia when administered in subanesthetic doses to human volunteers suffering acute, experimentally induced ischemic pain. S-Ketamine was 4 times more potent than R-ketamine as an analgesic agent in this model system. The relative order of analgesic potency of the two enantiomers was compared to their relative affinity for phencyclidine (PCP) binding sites (associated with the NMDA receptor-operated ion channel) and for sigma binding sites (which are not associated with the NMDA receptor complex). The relative analgesic potency of the enantiomers correlated positively with their relative affinity for PCP sites and negatively with their relative affinity for sigma sites. The results strongly indicate that PCP sites, but not sigma sites, are functional receptors mediating the analgesic effect of ketamine. This is consistent with the hypothesis that NMDA receptors are essential for pain perception in humans. Disturbances of other sensory modalities, in particular somatosensory perception, vision and hearing, were the main side-effects observed. These effects were qualitatively similar for both enantiomers and were closely associated with their analgesic action. The NMDA type of excitatory amino acid receptor thus appears to be widely involved in the processing of sensory afferent signals in the human brain.
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PMID:Evidence of a role for NMDA receptors in pain perception. 196 98

Ketamine has been employed as an anesthetic for 25 years. It is the only PCP-like dissociative anesthetic in clinical use. Favourable experience with ketamine in combat situations and at accidents, together with its ability to block the effect of the excitatory neurotransmitter glutamate on NMDA-receptor mediated neurotransmission, has attracted greater attention to this drug in recent years. The indications for and the use of ketamine as an anesthetic is described, and its various side-effects discussed. Combination with benzodiazepines greatly reduces these side-effects. Several pharmacological mechanisms may contribute to the effects of ketamine, in particular when large (anesthetic) doses are given. Recent investigations indicate that the analgesic and anesthetic effects as well as the "dissociative" phenomena seen after analgesic doses are due to PCP receptor mediated inhibition of excitatory amino acid transmission at NMDA synapses. The excitatory effect observed at higher doses, however, may be mediated by the haloperidol sensitive sigma-receptor. The enantiomers of ketamine (R- and S-ketamine) differ in pharmacological profile and may enable improvement of ketamine as a drug.
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PMID:[Ketamine: clinically useful--pharmacologically interesting]. 216 88

Ketamine, a congener of phencyclidine (PCP), can produce a range of psychological effects which have led to its nonmedical use. Recent discoveries concerning the effects of ketamine and similar substances in the brain suggest that they may interfere with memory processes when given acutely and may affect synaptic plasticity when given chronically in high doses in certain animal models. It is thus of interest to examine the consequences, if any, of chronic use in humans. A case is here presented of long-term, high-dose ketamine use, in which the user described impaired recall and attention, and a subtle visual anomaly persisting after cessation of the habit. This history is considered in the context of other relevant studies.
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PMID:Ketamine--can chronic use impair memory? 222 29

Among other properties, phencyclidine (PCP) and analogues display anaesthetic and anticonvulsant properties. Interaction of PCP and some analogues with the voltage-sensitive Na+ channels have been investigated and compared with their interaction with the PCP receptor. PCP and TCP inhibit apparently in a competitive manner the veratridine stimulated 22Na+ synaptosomal uptake with Ki values of 8.6 and 12.7 microM, respectively, close to those obtained in the inhibition of [3H]BTX-B binding (IC50 = 4.1 and 3.8 microM, respectively). The specific [3H]TCP binding to synaptosomes in ionic near physiological conditions is inhibited by PCP and TCP with IC50 values of 1.25 and 0.29 microM, respectively. Other PCP derivatives (GK3 and GK4) and PCP-like drugs (ketamine and MK801) inhibit 22Na+ uptake in an order of potency (GK3 greater than GK4 greater than PCP greater than TCP greater than MK801 greater than ketamine) which is different from that obtained in the inhibition of [3H]TCP binding (MK801 greater than TCP greater than PCP greater than ketamine greater than GK4 greater than GK3). Ketamine inhibits the veratridine-stimulated Na+ uptake at a concentration where its anesthetic effect occurs. It was concluded that the interaction of these drugs with the Na+ channel may reflect their anaesthetic properties while the interaction with the PCP receptors may be mainly related to their anticonvulsant and ataxic properties.
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PMID:Anaesthetic properties of phencyclidine (PCP) and analogues may be related to their interaction with Na+ channels. 254 67

1. The effects caused by the dissociative anaesthetic drugs (PCP, KT), the sigmaopiates (SKF 10.047, cyclazocine), and the mixed excitatory amino acid antagonist CCP on the electrical activity of the red nucleus in rabbits were compared with PB. 2. Ketamine (10 mg/kg, i.v.) induced the appearance of a pentobarbital-like EEG synusoidal rhythm characterized by an increase in amplitude and a decrease in frequency of the basal electrical activity at the red nucleus level. 3. Both pentobarbital and ketamine induced rhythms were blocked by the GABA-antagonist pentylenetetrazol at the subconvulsant dose of 10 mg/kg, i.v. 4. Phencyclidine, SKF 10.047, cyclazocine, and the mixed excitatory amino acid antagonist CCP failed to affect the basal electrical activity of the red nucleus. 5. These data indicate an interaction of ketamine on the GABA neurotransmission at the level of cerebello-rubral pathways which the other PCP/sigma opiates did not present.
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PMID:Pentobarbital-like electroencephalographic rubral rhythm induced by ketamine in rabbits. 254 79

The high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.
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PMID:The effects of non-competitive NMDA receptor antagonists on rats exposed to hyperbaric pressure. 254 78

1. In electrophysiological experiments in spinalized rats, mu- and kappa-opioids were tested intravenously on the responses of single motoneurones to electronically controlled, alternating noxious heat and noxious pinch stimuli. The effects of mu- and kappa-opioids were compared with those of the general anaesthetic alpha-chloralose and the dissociative anaesthetic/PCP ligand ketamine. 2. The kappa-opioids U-50,488 (0.5-16 mgkg-1 i.v.) and tifluadom (0.05-1.6 mgkg-1 i.v.) had very similar actions to the mu-opioid fentanyl (0.5-16 micrograms kg-1 i.v.). Thus all three agonists reduced thermal and mechanical nociceptive reflexes in parallel and in a dose-dependent manner, but only so long as neuronal responses to the alternating stimuli elicited similar excitability levels in the neurone under study. Ketamine (0.5-16 mgkg-1 i.v.) had similar actions to the opioids whereas alpha-chloralose (20 mgkg-1 i.v.) had very little effect on neuronal responsiveness. 3. Apparently 'selective' depressions by both mu- and kappa-opioids could be orchestrated by a deliberate mismatch of the intensities of alternating noxious heat and pinch stimuli; as measured by neuronal firing rate, the weaker of the responses to either type of stimulus was invariably reduced to a greater degree. 4. Similar 'selectivity' could be demonstrated for both mu- and kappa-ligands when the weaker and stronger responses were of the same modality, being applied by the same pincher device but with alternating applied force. 5. It is concluded that the 'selective' spinal actions of kappa-opioids seen in non-thermal over thermal behavioural models of nociception is likely to be related to the relative intensities, rather than the modalities, of the noxious stimuli used. The validity of the interpretation of results obtained in such behavioural studies is discussed.
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PMID:Spinal antinociceptive actions of mu- and kappa-opioids: the importance of stimulus intensity in determining 'selectivity' between reflexes to different modalities of noxious stimulus. 255 11

Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalize in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-phosphonoheptanoic acid (2-APH), also resulted in a dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antagonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [3H](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive sigma recognition site in the behaviour.
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PMID:A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine. 282 52


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