piperidines and 1-hydroxy-3-amino-2-pyrrolidone

Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined.. The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.

Topics: Analgesia; Analgesics, Opioid; Animals; Central Nervous System; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Isoquinolines; Male; Methadone; Mice; Mice, Inbred C57BL; Morphine; Nociceptors; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrrolidinones; Reaction Time; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

Treatments for Parkinson's disease based on replacement of lost dopamine have several problems. Following loss of dopamine, enhanced N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the striatum is thought to be part of the cascade of events leading to the generation of parkinsonian symptoms. We determined the localisation and pharmacological characteristics of NMDA receptors that play a role in generating parkinsonian symptoms within the striatum. Rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and cannulae implanted bilaterally to allow injection of a range of NMDA receptor antagonists at different striatal sites. When injected rostrally into the dopamine-depleted striatum, the glycine site partial agonist, (+)-HA-966 (44-400 nmol) caused a dose-dependent contraversive rotational response consistent with an antiparkinsonian action. (+)-HA-966 (400 nmol) had no effect when infused into more caudal regions of the dopamine-depleted striatum, or following injection into any striatal region on the dopamine-intact side. To determine the pharmacological profile of NMDA receptors involved in inducing parkinsonism in 6-OHDA-lesioned rats, a range of NMDA receptor antagonists was infused directly into the rostral striatum. Ifenprodil (100 nmol) and 7-chlorokynurenate (37 nmol), but not MK-801 (15 nmol) or D-APV (25 nmol) elicited a dramatic rotational response when injected into the dopamine-depleted striatum. This pharmacological profile is not consistent with an effect mediated via blocking NR2B-containing NMDA receptors. The effect of intrastriatal injection of ifenprodil was increased in animals previously treated with levodopa (L-dopa) methyl ester. This was seen as an increase in on-time and in peak rotational response. We propose that stimulation of NR2B-containing NMDA receptors in the rostral striatum underlies the generation of parkinsonian symptoms. These studies are in line with previous findings suggesting that administration of NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients, when given de novo and following L-dopa treatment.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Levodopa; Male; Microinjections; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Previous research has demonstrated that intrathecal i.t. morphine in a dose of 60.0 nmol into the spinal subarachnoid space of mice can evoke nociceptive behavioral responses consisting of a severe hindlimb scratching directed toward the flank followed by biting/licking of the hindpaw. The present study was undertaken to examine the involvement of spinal N-methyl-D-aspartate (NMDA) and opioid receptors on the behavioral responses evoked by high-dose i.t. morphine. Pretreatment with naloxone, an opioid receptor antagonist (1.0 and 4.0 mg/kg, s.c.), failed to reverse the morphine-evoked behavioral response, suggesting that the morphine effect is not mediated through the opioid receptors in the spinal cord. The morphine-induced behavior was dose-dependently inhibited by i.t. co-administration of the competitive NMDA receptor antagonists, D(-)-2-amino-5-phosphonovaleric acid (D-APV) (6.25-50.0 pmol) and 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (3.125-25.0 pmol). The characteristic behavior was also reduced by co-administration of (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate (MK-801) (74.1-250 pmol), an NMDA ion-channel blocker. Ifenprodil, a competitive antagonist of the polyamine recognition site of NMDA receptor ion channel complex, produced a dose-related inhibitory effect on the behavioral response to i.t. morphine with less potency than the competitive and non-competitive antagonists examined. High doses of (+)-HA-966, a glycine/NMDA antagonist, induced a dose-dependent inhibition of morphine-induced response. The effective dose of i.t. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, needed to reduce the morphine-induced response, was approximately 10-fold greater than that of D-APV. These results suggest that spinal NMDA receptors, but not non-NMDA receptors, may be largely involved in elicitation of the behavioral episode following i.t. injection of morphine in mice.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Binding, Competitive; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Hindlimb; Hyperalgesia; Injections, Spinal; Male; Mice; Mice, Mutant Strains; Morphine; Naloxone; Narcotic Antagonists; Nerve Tissue Proteins; Pain Measurement; Piperazines; Piperidines; Pyrrolidinones; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Spinal Cord; Subarachnoid Space

Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine's discriminative stimulus and response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R(+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The development of tolerance to morphine's stimulus effects was attenuated by eliprodil and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists prevented the induction of tolerance to morphine's response rate effects. Dizocilpine and D-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.

Topics: Animals; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Excitatory Amino Acid Antagonists; Male; Morphine; Narcotics; Piperazines; Piperidines; Pyrrolidinones; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate

This study examined the effects on rat behaviour of antagonists acting at various sites on the N-methyl-D-aspartate (NMDA) receptor complex, i.e. the glutamate recognition site (CPP), ion channel (dizocilpine), glycine recognition site [(+)-HA-966] and the NR2B subunit-selective compound ifenprodil. Specifically, the effects of these agents were examined on working memory, assessed using the operant delayed match-to-position task (DMTP), and overt behaviour, assessed (a) in animals responding for food under a variable interval 20-s (VI20) schedule and (b) by spontaneous behaviour. Dizocilpine, CPP and (+)-HA-966 each reduced accuracy in the DMTP task independent of delay. At equivalent doses, changes in locomotor behaviour and VI20 responding were evident. In contrast, ifenprodil failed to impair accuracy in the DMTP task, even at doses that affected other performance measures and reduced VI20 responding. The relevance of these observations to neuroprotective and anticonvulsant doses of these compounds is considered.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memory, Short-Term; Motor Activity; Piperazines; Piperidines; Pyrrolidinones; Rats; Receptors, N-Methyl-D-Aspartate; Reinforcement Schedule

We have recently demonstrated that a single administration of m-chlorophenylpiperazine (m-CPP, a preferential 5-HT2C receptor agonist) produces tolerance to its stimulatory effect on adrenocorticotropic hormone (ACTH) concentrations when challenged 24 h later with the same dose of m-CPP. In the present study, we studied the effects of pretreatment with various N-methyl-D-aspartate (NMDA) receptor antagonists on development of tolerance to m-CPP's stimulatory effect on ACTH concentrations. Pretreatment with various NMDA receptor antagonists such as 5.7-dichlorokynurenic acid (1.0 mg/kg), 3-amino-1-hydroxy 2-pyrrolidone (1.0 mg/kg), dizocilpine (0.1 mg/kg) and ifenprodil (1.0 mg/kg) injected 30 min before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 h later with the same dose (2.5 mg/kg) of m-CPP. These findings suggest that tolerance to postsynaptic 5-HT2C receptor-mediated response is initiated though stimulation of NMDA receptor complex and, furthermore, demonstrate a functional interaction between the 5-HT and glutamate systems.

Topics: Adrenocorticotropic Hormone; Animals; Dimethyl Sulfoxide; Dizocilpine Maleate; Drug Tolerance; Kynurenic Acid; Male; Phencyclidine; Piperazines; Piperidines; Pyrrolidinones; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Serotonin Receptor Agonists

The strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1, 2-cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizoclipine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Ibogaine; Male; Mice; Piperidines; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Strychnine

The tachykinin receptor antagonists (3aR,7aR)-7,7-diphenyl-2(1-imino-2-(2-methoxyphenyl/ethyl)++ +perhydroisoindole) (RP 67580) and (+)-(2S-3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), which act selectively at neurokinin (NK)1 receptors, inhibited the early phase of formalin-induced pain in mice. Although (+)-(1-hydroxy-3-aminopyrrolidine-2-one) ((+)-HA966), a partial agonist at glycine B receptors, was inactive alone, it potentiated the actions of RP 67580 (but not its inactive stereoisomer, RP68651) and CP-99,994. In its presence, the dose-response curve for RP 67580 was dose-dependently shifted to the left. In contrast, (+)-HA966 did not modify the induction of ataxia by RP 67580 and CP-99,994. These data suggest that co-administration of partial agonists at glycine B receptors may improve the antinociceptive potency and 'therapeutic window' of tachykinin NK1 receptor antagonists.

Topics: Analgesics; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Synergism; Glycine; Indoles; Isoindoles; Male; Mice; Piperidines; Pyrrolidinones; Receptors, Glycine; Receptors, Tachykinin

The non-competitive N-methyl-D-aspartate (NMDA) antagonists (channel blockers), MK 801, phencyclidine (PCP) and ketamine induced spontaneous tail-flicks in rats. Their order of relative potency (MK 801 greater than PCP greater than ketamine) corresponds to their relative affinities for the ion channel coupled to NMDA receptors. Drugs interacting with their other potential targets (sigma receptors as well as dopamine, serotonin and noradrenaline uptake sites) failed to induce spontaneous tail-flicks. In addition, the catecholamine stimulants, methylphenidate and cocaine were inactive. CPP and CGS 19755, antagonists at the NMDA recognition site, also dose dependently elicited spontaneous tail-flicks: their maximal effect was equal to that of the channel blockers. In contrast, HA-966 and ifenprodil, putative antagonists at the glycine and polyamine recognition sites, respectively, failed to elicit spontaneous tail-flicks. These data demonstrate that both antagonists of the NMDA recognition site and non-competitive blockers of the associated channel induce spontaneous tail-flicks in rats.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ion Channels; Ketamine; Male; N-Methylaspartate; Organophosphorus Compounds; Phencyclidine; Pipecolic Acids; Piperazines; Piperidines; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate