Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.
 ...
PMID:The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. 94 47

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)
 ...
PMID:Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs. 168 18

Effects of opioid kappa agonist ethylketazocine (EKC), sigma agonist (+-)-N-allylnormetazocine (NANM), and naloxone alone and in combination on mean blood pressure (MBP), heart rate (HR), respiratory rate (RR) and minute volume (MV) were studied in acutely decerebrated dogs. EKC (0.5 mg/kg) decreased HR, MBP, RR and MV. Post-EKC NLX increased RR and MV and reversed the bradycardia and hypotension produced by EKC. NANM (1 mg/kg) produced respiratory depression and tachycardia without changing MBP. Post-NANM NLX antagonized tachycardia, increased MBP, however did not significantly change RR and MV. When decerebrate dogs were spinalized at the C-1 level, EKC decreased MBP and HR. These effects were antagonized by NLX. NANM did not change HR but raised MBP in spinalized decerebrate dogs. Since EKC- and NANM-induced cardiovascular and respiratory depression were not observed in conscious intact or chronic spinal dog, it is suggested that: 1) kappaergic system rostral to mesencephalon may play a role in counteracting these depressant effects of EKC; 2) sigma receptor-mediated tachypnea and tachycardia are dissociable; the tachypneic effect may be mediated through higher center while the medulla oblongata is involved in producing tachycardia. These results also suggest that (+-)-NANM probably has several mechanisms of action at several brain sites in producing its effects on respiration and cardiovascular function.
 ...
PMID:Cardiovascular and respiratory effects of an opioid kappa agonist ethylketazocine and sigma agonist N-allylnormetazocine in acutely decerebrated dogs. 269 44

The purpose of this experiment was to investigate the interaction of GABA (gamma aminobutyric acid) with PCP (phencyclidine) and sigma receptor agonists in the cerebellum. Drugs were applied directly to a single cerebellar Purkinje neuron of urethane-anesthetized rats, through a multibarrel pipette. The PCP receptor agonist, (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], significantly enhanced GABA-induced inhibition. On the other hand, its stereoisomer, (-)PCMP, had no such modulatory effect. Dexoxadrol, a sigma receptor agonist, similar to (+)PCMP, potentiated GABA-induced depression. Its stereoisomer, levoxadrol, although inhibiting the spontaneous firings of Purkinje neurons, did not alter the effect of GABA. In conclusion, the findings indicate that the electrophysiological mechanisms of PCP-induced facilitation of GABA-induced reactions are similar to those triggered by sigma agonists in the cerebellum.
 ...
PMID:Facilitation of gamma-aminobutyric acid-induced depression by (+)PCMP and dexoxadrol in the cerebellar Purkinje neurons of the rat. 274 47

The agonist/antagonist analgesics, butorphanol (Stadol) and nalbuphine (Nubain), are being increasingly employed as intravenous sedation agents; nalbuphine will be available in the future as an oral analgesic. The drugs possess numerous pharmacologic similarities and some dissimilarities. Both are equianalgesic (and nalbuphine is equipotent) with morphine parenterally and codeine orally. Their pharmacokinetics are similar; nalbuphine has a longer duration of action. Both may precipitate an abstinence syndrome in narcotic-dependent persons and will probably be associated with low-level drug abuse potential. They are both agonists of the kappa opioid receptor and partial agonists of the mu receptor. Butorphanol is a partial agonist of the sigma receptor responsible for psychotomimetic effects. The incidence of adverse effects is low, sedation being the most common. In cardiac-risk patients, nalbuphine does not increase cardiac work or oxygen requirements; nor do increasing doses of nalbuphine increase the duration of respiratory depression. Both drugs possess plateau respiratory depressant actions.
 ...
PMID:Butorphanol and nalbuphine: a pharmacologic comparison. 298 81

Analgesics such as morphine are toxic drugs that kill by producing respiratory depression. Further morphine-like drugs produce a high level of physical dependence and are highly reinforcing in some subjects. A systematic search, conducted over the last 50 years, for safer and less addicting analgesic has revealed that opioid analgesics act on different types of opioid receptors (mu, kappa, and sigma), and that they may function as mixed agonist-antagonists or as partial agonists. Thus some mixed agonists function as competitive antagonists at the mu receptor and as partial or strong agonists at the kappa or sigma receptor. When mixed agonists produce the same pharmacologic effects (eg, analgesia) by acting on different receptors, they invoke the principle of receptor dualisms. Drugs that produce agonist (analgesic) effects by acting on the kappa receptors are an order of magnitude safer than the mu agonists and produce a lesser degree of physical dependence than strong mu agonists. Thus safer, less addicting analgesics have been produced that act either as agonist-antagonists or by being partial agonists.
 ...
PMID:Clinical evidence for different narcotic receptors and relevance for the clinician. 301 58

The interactions of phencyclidine (PCP) and related agonists with putative receptor blockers were studied on cerebellar Purkinje neurons using electrophysiological techniques. Depressions induced by PCP or dexoxadrol, a sigma receptor agonist, were markedly antagonized by the PCP receptor antagonist metaphit, which acylates PCP receptors via its isothiocyanate moiety. Conversely, the depressant effect of levoxadrol, the (-) isomer of dexoxadrol, was not affected by metaphit. Further evidence that metaphit's specific antagonism of dexoxadrol- and PCP-mediated depressions was derived from data showing that drugs which respectively acylate mu and delta opioid receptors, benzimidazole isothiocyanate and fentanyl isothiocyanate, do not antagonize the actions of either PCP or dexoxadrol. Moreover, tyramine, which like PCP acts as an indirect norepinephrine agonist, is not antagonized by metaphit. These observations support the concept that metaphit causes a pharmacologically specific and irreversible antagonism of the effects of both PCP and dexoxadrol in the cerebellum. Thus, the electrophysiological mechanisms of PCP actions are similar to those triggered by sigma opioid agonists in this brain area.
 ...
PMID:Interactions of metaphit with phencyclidine and sigma agonist actions in rat cerebellum: determination of specificity and selectivity. 303 7

Neuropeptide Y is a 36-amino acid peptide that is widely distributed in the brain. Recently, three neuropeptide Y receptor subtypes were discovered with the aid of peptidergic agonist analogs of neuropeptide Y. Many researchers reported that neuropeptide Y might be involved in locomotor activity, eating behavior, stress responses, memory processing, circadian rhythms, blood pressure and neuroendocrine functions. It was also reported to interact with sigma receptor and corticotropin-releasing factor. Clinical evidence suggests that neuropeptide Y might be related to depression, schizophrenia, anorexia nervosa and Alzheimer's disease. In this review, central distribution and receptor subtypes of neuropeptide Y, its physiological action and its levels in cerebrospinal fluid and plasma in psychiatric and neurological illnesses are described.
 ...
PMID:[Neuropeptide Y: psychopharmacological and clinical aspects]. 794 76

1. The effects of 1,3-di(2-tolyl)guanidine (DTG) were examined on the responses of cultured hippocampal neurones to the excitatory amino acid analogues N-methyl-D-aspartate (NMDA), kainate, quisqualate and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). 2. In rat hippocampal neurones loaded with the Ca(2+)-sensitive dye Fura-2, DTG (10-100 microM) produced a concentration-dependent depression of the NMDA-evoked rises in intracellular free calcium ([Ca2+]i), an effect that was not modified by changes in the extracellular glycine concentration. DTG (at 50 and 100 microM) also attenuated, although to a lesser extent, the rises in [Ca2+]i evoked by naturally-derived quisqualate. In contrast, 50 and 100 microM DTG did not depress responses evoked by kainate, AMPA and synthetic, glutamate-free (+)-quisqualate although on occasions DTG enhanced kainate- and AMPA-evoked rises in [Ca2+]i. 3. DTG attenuated NMDA-evoked currents recorded from mouse hippocampal neurones under whole-cell voltage-clamp with an IC50 (mean +/- s.e. mean) of 37 +/- 5 microM at a holding potential of -60 mV. The DTG block of NMDA-evoked responses was not competitive in nature and was not dependent on the extracellular glycine or spermine concentration. The block did, however, exhibit both voltage-, and use-, dependency. The steady-state current evoked by naturally-derived quisqualate was also attenuated by DTG whereas those evoked by kainate and AMPA were not. 4. We conclude that DTG, applied at micromolar concentrations, is a selective NMDA antagonist in cultured hippocampal neurones, the block exhibiting both Mg(2+)- and phencyclidine-like characteristics. Given the nanomolar affinity of DTG for sigma binding sites it is unlikely that the antagonism observed here is mediated by sigma-receptors, but the data emphasize the potential danger of ascribing the functional consequences of DTG administration solely to sigma receptor-mediated events.
 ...
PMID:Selective reduction of N-methyl-D-aspartate-evoked responses by 1,3-di(2-tolyl)guanidine in mouse and rat cultured hippocampal pyramidal neurones. 840 30

Psychological stress is believed to be implicated in the etiology of affective disorders such as anxiety and depression. To date, a wide range of behavioral responses including analgesia and motor suppression induced by various physiological stressors such as footshock, forced swimming and immobilization have been investigated in animals. However, there is little information concerning behavioral changes in psychological stress. This article describes the experimental procedures and the characteristics of motor suppression in psychological stress, defined as conditioned fear stress (CFS). Mice exhibit a marked suppression of motility when they are re-placed in the same environment in which they had previously received an electric footshock. This motor suppression is regarded as a conditioned emotional response to the environment associated with previous footshock. The motor suppression in CFS is attenuated by sigma receptor agonists such as (+)-N-allylnormetazocine and dextromethorphan, whereas typical anxiolytics (diazepam and chlordiazepoxide) and antidepressants (imipramine and fluoxetine) have no effect. These findings suggest that the CFS model may be useful for investigating the pathogenesis of affective disorders, particularly those considered to be treatment resistant, and for developing their novel therapeutic drugs.
 ...
PMID:[The psychological stress model using motor suppression]. 1020 85


1 2 3 Next >>