Antiaggressive action of atypical antipsychotics in patients with schizophrenia.
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Aggression↗
Biomedical subjects
C Advokat
Publications and source records attributed to C Advokat.
Antipsychotic medication and smoking prevalence in acutely hospitalized patients with chronic schizophrenia.
The atypical antipsychotic, clozapine, has been reported to reduce smoking in schizophrenic patients. We sought to determine whether other atypical antipsychotics would also be associated with a decreased prevalence of smoking in this population. Data were obtained from three groups of chronic, hospitalized, schizophrenic patients, receiving either a typical antipsychotic (n=15), clozapine (n=6), or another atypical antipsychotic (n=18). In addition to smoking prevalence, the groups were compared with regard to demographics (age, education), medication (doses, duration of treatment, side-effects), clinical (diagnosis, duration of illness) and behavioral (Wide-Range Achievement Test, Wechsler Adult Intelligence Scale) variables. Smoking prevalence differed significantly among the three groups (P<0.001). Clozapine was associated with a significantly lower incidence of smoking than either typical drugs (P<0.003) or other atypical antipsychotics (P=0. 042). The groups did not differ on demographic or other medication variables or on any of several behavioral measures. However, a diagnosis of paranoid schizophrenia was also significantly correlated with smoking (P<0.01), but not with medication class. Although the cause is still unknown, these results are consistent with reports that clozapine reduces smoking and provide new data on smoking prevalence associated with other atypical agents.
Acute Disease↗
Pentobarbital-induced modulation of flexor and H-reflexes in spinal rats.
Electrophysiological recordings of the H-reflex and nonnociceptive flexion reflex were obtained from pentobarbital-anesthetized Intact rats and from both, anesthetized and unanesthetized groups of Acute and Chronic Spinal rats. Results showed that the flexor, but not H-reflex, of Chronic Spinal rats was significantly larger than that of all other groups, which did not differ among themselves. The antispastic drug baclofen dose-dependently decreased the flexion response of Chronic Spinal rats (A(50)=4.3 mg/kg+/-2.1 and 9.0 mg/kg).
Adjuvants, Anesthesia↗
Dual localization of neuropeptide FF receptors in the rat dorsal horn.
Although neuropeptide FF (NPFF) is generally considered an anti-opioid, its intrathecal administration produces analgesia. In the present study, the stable analog 1DMe ([D.Tyr(1), (NMe)Phe(3)]neuropeptide FF) was used in quantitative autoradiographic experiments in combination with surgical and chemical lesions to precisely localize NPFF receptors in the rat spinal cord. Ligation of lumbar dorsal spinal roots revealed the presence of NPFF receptors in dorsal root fibers and it induced a significant accumulation of [(125)I]1DMe-specific binding on the side peripheral to the ligature, demonstrating that a population of NPFF receptors is synthesized in dorsal root ganglia and migrates anterogradely towards primary afferent nerve endings. Complete mid-thoracic spinal cord transection failed to modify the [(125)I]1DMe labeling density in the dorsal horn, indicating that NPFF receptors are not located on the descending fiber terminals. In contrast, unilateral microinjections of kainic acid into the dorsal horn dramatically reduced [(125)I]1DMe-specific binding in the superficial layers, revealing localization of a population of NPFF receptors on the spinal intrinsic neurons. NPFF receptor binding was not modified during the development of spinal opioid tolerance. The pre- and postsynaptic localization of spinal NPFF receptors provide further support for heterogeneity in the pain modulation by NPFF and related agonists.
Analgesics, Opioid↗
Dissociation of (-) baclofen-induced effects on the tail withdrawal and hindlimb flexor reflexes of chronic spinal rats.
We previously reported that the antinociceptive effect of the GABA(B) receptor agonist, (-)baclofen, in chronic spinal rats depended on the route of administration. That is, subcutaneous (SC) injections significantly increased the latency of the thermally elicited tail withdrawal (tail flick, TF) reflex, whereas spinal (intrathecal, IT) injections did not. The present studies attempted to determine the reason for this differential response. The possible contribution of a peripheral component to the systemic effect was evaluated, but was not supported by negative results of intradermal (-)baclofen injections (50 and 500 microg) into the tail skin of chronic spinal rats. A spinal site of action was indicated when pretreatment with 30 microg, IT of the GABA(B) receptor antagonist, phaclofen, significantly reduced the antinociceptive effect of SC (-)baclofen in both chronic spinal (5 mg/kg) and intact rats (2 mg/kg). Moreover, direct IT injections of (-)baclofen in chronic spinal rats produced a modest, but statistically significant increase in TF latency at doses of 0.06, 0.12, 0.3, and 0.6 microg, but not 1.2 microg. In the same spinal preparation, the flexor response was significantly reduced by IT injection of 0.6 and 1.2 microg, but not lower doses of 0.3 and 0.12 microg. These results provide the first quantitative, electrophysiological evidence of an antispastic effect of IT (-)baclofen in an in vivo, unanesthetized animal model. Second, the data show a separation between an antinociceptive effect of low spinal doses and an antispastic/muscle relaxant effect at higher doses, which may account for the results of our prior report. Finally, the data are also consistent with behavioral reports of antiallodynic/analgesic effects of low-dose baclofen, and may be relevant to the electrophysiological evidence of a preferential presynaptic action of low-dose (-)baclofen at the primary afferent synapse.
Analgesics↗
Comparison of morphine-induced effects on thermal nociception, mechanoreception, and hind limb flexion in chronic spinal rats.
The effect of systemic morphine on 3 behaviors in the same group of chronic spinal rats was examined: the tail-flick (TF) reflex to a noxious thermal stimulus, limb withdrawal (LW) to mechanoreceptor (von Frey hair) stimulation, and hind limb flexion (flexor reflex [FR]) elicited by innocuous electrical stimulation of the toes. Compared with intact rats, the potency of morphine on both the TF and the hind paw (but not the forepaw) LW response was significantly reduced. Morphine's effect on the FR depended on the dose. The lowest dose (1.0 mg/kg) produced no change, 4.0 mg/kg decreased response magnitude by approximately 50% (indicating an antispastic effect), and 8.0 mg/kg increased flexor magnitude by 100%. The concurrent TF and FR assays revealed a dissociation of morphine's effects in that the highest dose (8.0 mg/kg) significantly inhibited the nociceptive TF response but facilitated the FR in the same chronic spinal rats. This outcome may be relevant to the phenomenon of "opioid-related myoclonus" recently described in cancer patients, which "was highly associated with nerve dysfunction due to spinal cord lesions" (S. Mercadante, 1998, p. 6).
Animals↗
Morphine and dextrorphan lose antinociceptive activity but exhibit an antispastic action in chronic spinal rats.
Within 3-4 weeks after spinal transection, morphine-induced antinociception, assessed with the tail flick reflex in rats, is profoundly reduced. The cause of this decrement is unknown. The present studies were conducted to determine whether this phenomenon reflects a general loss in opiate activity or a selective decline in opiate antinociception. This was accomplished by assessing the effect of morphine on two different responses, the tail flick reflex and the hindlimb spasticity that develops in chronic spinal rats. Because excitatory amino acid antagonists are also antinociceptive in acute spinal rats, the effect of one such drug, dextrorphan, on these two behaviors was also evaluated in chronic spinal animals. The antinociceptive and antispastic effect of subcutaneous (6 mg/kg) and intrathecal (5 micrograms) morphine injections were assessed in intact and chronic (21-28 days) spinal rats, whereas the effect of subcutaneous (25 and 40 mg/kg) and intrathecal (350 micrograms) dextrorphan was assessed in acute (1 day) and chronic spinal rats. The antinociceptive effect of both drugs was significantly reduced in chronic spinal animals, relative to saline controls. However, each drug treatment produced a significant antispastic effect in the same animals, indicating a selective decline in opiate action. This outcome also suggests that excitatory amino acid antagonists may be useful as adjunct antispastic agents.
Animals↗
Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan.
Neurophysiologic and behavioral evidence indicates that excitatory amino acid (EAA) antagonists may provide a new class of selective analgesics for opiate resistant, neuropathic pain syndromes. Therapeutic applications have been limited because of unacceptable side effects of most EAA blockers. However, dextrorphan, a metabolite of the antitussive drug, dextromethorphan, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of EAA receptor with few side effects and a moderate analgesic effect in animals with peripheral neuropathy. It may therefore, have clinical benefit, either alone or in combination with opiates, for neuropathic pain. In this study a subeffective dose of dextrorphan (15 mg/kg) was combined with several doses of morphine (1.5, 3.0 and 6.0 mg/kg) and assessed in an animal model of central injury, the tail flick response of the acute spinal rat. At doses which were individually ineffective, the combination of dextrorphan and morphine (15 and 1.5 mg/kg, respectively) produced a significant antinociceptive response. The same dose of dextrorphan also increased the antinociceptive response to 3.0 and 6.0 mg/kg of morphine. Coadministration of low doses of an NMDA antagonist and an opiate, might have clinical benefit for the relief of pain with reduced risk of undesirable side effects.
Animals↗
Comparison of the antinociceptive and antispastic action of (-)-baclofen after systemic and intrathecal administration in intact, acute and chronic spinal rats.
Baclofen is particularly effective in treating spasticity of spinal origin in humans. However, most investigations of this drug in animals have only assessed its antinociceptive effect, presumably because of the difficulty in developing animal models of spasticity. This study attempted to evaluate both, the antinociceptive and antispastic action of (-)-baclofen (the more active enantiomer) by incorporating the chronic spinal preparation, in which spasticity gradually develops following spinal transection. Separate groups of intact, acute (1 day) or chronic (20-25 days) spinal rats were pretested on the nociceptive tail-flick (TF) assay prior to either subcutaneous (SC; 1-30 mg/kg) or intrathecal (IT; 0.1-12 micrograms) injection of (-)-baclofen and retested at specific post-injection intervals. Hindlimb spasticity was elicited in chronic spinal rats by mechanical stimulation to the abdomen. Because the clinical use of baclofen generally involves chronic administration, both responses were tested for 3 successive days to assess tolerance. Results confirmed the analgesic effect of SC and IT (-)-baclofen in intact rats. As previously reported, the antinociceptive effect of IT (-)-baclofen was increased in acute spinal rats. However, three weeks after spinalization there was a profound decrease in this response. In contrast, antinociception produced by SC (-)-baclofen was reduced in acute and chronic spinal rats compared to intact animals; but there was no difference between the acute and chronic conditions. In spite of this differential decrease in antinociception after IT, relative to SC, administration, both routes of administration produced an antispastic effect in chronic spinal rats. There was no antinociceptive tolerance to SC administration and only minimal tolerance to IT (-)-baclofen (in intact rats); the antispastic effect did not become tolerant. A peripheral action might explain the dichotomy between SC and IT (-)-baclofen in regard to antinociception. However, further research is needed to determine why both routes of administration were effective against spasticity while only SC (-)-baclofen retained an antinociceptive action in chronic spinal rats.
Animals↗
Selective antinociceptive effect of excitatory amino acid antagonists in intact and acute spinal rats.
Results of neurophysiologic and behavioral studies suggest that excitatory amino acid (EAA) antagonists may provide a new class of analgesic agents, which might be selective for neuropathic pain states that are resistant to opiate treatment. Most of these paradigms involve animal models of peripheral injury. The present study evaluated the antinociceptive effect of spinally [intrathecally (IT)] administered EAA antagonists after central injury, produced by spinal transection. Intrathecal injection of the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione produced dose-dependent antinociception on the thermal tail withdrawal [tail-flick (TF)] reflex test in Intact rats, which was significantly potentiated after spinal transection. In contrast, IT injection of the NMDA antagonist, 2-amino-5-phosphonopentanoic acid (AP5) did not affect the TF in intact rats, but significantly blocked this response in spinal rats. However, some of the spinal rats did not recover the reflex, suggesting a possible toxic action of AP5.
2-Amino-5-phosphonovalerate↗
Pharmacotherapy of the eating disorders: a commentary.
During the last 10 yr, evidence has accumulated which indicates that the eating disorders of bulimia and anorexia nervosa (BN and AN) may be differentially affected by pharmacological treatment. Although the efficacy of drug treatment alone (relative to nonpharmacological approaches) has been debated, there is support for the generalization that all types of antidepressant medications have proven efficacious for bulimia but not for anorexia. These clinical observations are consistent with an extensive body of research concerning the regulation of ingestion, which indicates that the neurotransmitter serotonin plays an important role in mediating satiety. Such considerations have led to the "serotonin-hypothesis of bulimia," which postulates that BN represents an underlying "hyposerotonergic" condition and, conversely, that AN represents a "hyperserotonergic" state. Recently, however, two independent studies have shown that the antidepressant fluoxetine, which selectively blocks the synaptic re-uptake of serotonin, provided significant therapeutic benefit for anorexic patients. The implications of these apparently anomalous results for the "serotonin-hypothesis of BN" are discussed in an attempt to gain insight into the present pharmacotherapy of the eating disorders.
Animals↗
Intrathecal co-administration of morphine and excitatory amino acid agonists produce differential effects on the tail-flick of intact and spinal rats.
Previous reports, that intrathecal morphine is more potent on the tail-flick test of acute spinal rats than intact rats, suggested that spinal opiate analgesia was attenuated by neurotransmitter release from descending pathways. To determine if this phenomenon involved excitatory amino acids (EAAs), 0.25 nm of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) were i.t. co-administered with morphine to Intact and Spinal rats. NMDA potentiated morphine antinociception in Intact but not Spinal rats; AMPA had no effect in Intact rats, but significantly reduced morphine antinociception in Spinal rats. The data suggest a reciprocal descending, modulatory influence on the spinal interaction between EAAs and morphine.
Animals↗
Intrathecal excitatory amino acid (EAA) agonists increase tail flick latencies (TFLs) of spinal rats.
The facilitation of spinal nociceptive reflexes that occurs after spinal transection reveals the existence of descending, supraspinally mediated inhibition. Substantial evidence indicates that the excitatory amino acids (EAAs) are involved in these spinal circuits. Therefore, it was hypothesized that reflex facilitation in the spinal animal might be due to the removal of inhibitory input normally exerted on the spinal action of EAAs. If so, the facilitatory decrease in reflex latency, observed in the spinal preparation, might be potentiated by intrathecal (IT) administration of EAA agonists. This was tested by comparing the effect of IT injections of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) on the thermally elicited tail flick (TF) response of Intact and acute spinal rats. In intact rats, a low (0.25 nM) dose of NMDA produced a hyperalgesic decrease in latency, relative to saline, whereas higher doses produced an overall increase in latency. A large dose (0.5 microM) produced overt signs of toxicity (crippling, self-mutilation, and loss of the reflex). Only the highest (1.0 nM) dose of AMPA affected the response, resulting in a significant increase. After spinal transection, the hyperalgesic reaction to 0.25 nM of NMDA was absent, and latencies were significantly increased by 1.0 nM. The toxic reaction to 0.5 microM appeared to be potentiated. Tail flick responses to AMPA were also significantly increased in spinal rats. Contrary to the prediction, reflex latencies were significantly increased by these drugs after spinal transection. It was suggested that, although the spinal action of EAAs appears to be supraspinally modulated, this influence may be facilitatory rather than inhibitory.
Animals↗
Evidence of a role for N-methyl-D-aspartate (NMDA) receptors in the facilitation of tail withdrawal after spinal transection.
Peripheral injury produces a characteristic excitation of spinal cord dorsal horn cells (wind-up) which is associated with a facilitation of spinal nociceptive reflexes (hyperalgesia). These phenomena are believed to be mediated by a trauma-induced increase in the release of excitatory amino acids (EAAs). A similar increase in the activity of dorsal horn neurons and spinal reflexes occurs after spinal transection. Therefore, the present studies examined the possibility that EAAs, acting through the NMDA receptor, might also be involved in behavioral hyperalgesia produced by central injury. The first experiment assessed the effect of pretreatment with the NMDA antagonist, ketamine, on the facilitated tail flick (TF) response of spinally transected rats. Separate groups of animals were spinalized under isoflurane anesthesia alone, intramuscular ketamine anesthesia alone, or a combination of isoflurane and intrathecal ketamine. The TF was examined 24 h later, before and 30 min after an intrathecal injection of morphine. In the second experiment, the effect of intraperitoneal or intrathecal ketamine on the TF was assessed to separate groups of rats that underwent spinal transection or sham surgery under isoflurane anesthesia. Pretreatment with either systemic or intrathecal ketamine did not alter TF facilitation or morphine-induced antinociception in spinal rats. However, both systemic and intrathecal ketamine significantly increased TF latencies in spinal, relative to intact rats. These results indicate that ketamine did not prevent the development of spinal reflex facilitation, but it selectively reduced this reaction once it was established in spinal rats. The data support an involvement of EAAs in reflex facilitation produced by spinal transection.
Analgesics↗
Intrathecal coadministration of serotonin and morphine differentially modulates the tail-flick reflex of intact and spinal rats.
In a previous study, we found that the antinociceptive effect of IT-administered morphine on the tail-flick (TF) reflex of rats was potentiated within 1 day after spinal transection. This suggested that the analgesic effect of spinal morphine in the intact animal was tonically suppressed, presumably by the release of a transmitter(s) from descending supraspinal pathway(s), and that the potency of IT morphine was increased because these inputs were removed by spinalization. Because spinally projecting serotonin [5-hydroxytryptamine (5-HT)] fibers are known to be involved in modulating nociception at this site, the present studies examined the possibility that 5-HT might be the proposed "antiopiate" at the spinal cord. Separate groups of intact and spinal rats were pretested on the TF and then injected IT with either morphine (intact: 0.25-5.0 micrograms, spinal: 0.0312-0.5 microgram) or 5-HT (1-200 micrograms), or combinations of these two agents, in a single solution. All rats were then retested 15 min later and the difference in latency was used to compare the effect of these treatments. The results confirmed that the antinociceptive effect of IT morphine was significantly increased by spinalization, whereas the antinociceptive effect of 5-HT was essentially abolished. In intact rats, morphine-induced analgesia was potentiated by a low (10 micrograms) dose of 5-HT but not by higher doses. However, in the spinal rat morphine-induced antinociception was antagonized by the same (10 micrograms) dose. The data suggest that IT 5-HT promotes antinociception in intact rats but acts pro-nociceptively in spinal rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Environmental modulation of behavioral tolerance in spinal rats.
We previously reported that the antinociceptive effect of morphine on the thermal tail withdrawal reflex (tail flick, TF) was reduced in rats that had practiced the TF response prior to morphine administration. This phenomenon, termed behavioral tolerance, was observed even when rats were spinally transected following the TF tests. The present experiments were conducted to determine whether such retention of behavioral tolerance after spinal transection was dependent on prior experience with the TF procedure, or whether other nociceptive pretreatments would also reduce opiate antinociception on the TF test in spinal rats. Separate groups of rats were pretreated with either nociceptive thermal TF or Hot Plate (HP), or mechanical Tail Pinch (TP) stimuli, as well as non-nociceptive exposure to the experimental context )Habituation) or No Pretreatment. Approximately half of the rats were spinally transected after their respective pretreatment, while the other half were left intact. When Intact rats were subsequently tested on the TF at 30, 60, 120 and 180 min after morphine administration, only the TF pretreated group was tolerant, relative to the Non-pretreated control group. However, this was a transient effect, and was only significant at the first, 30-min test; there was no difference among the groups in the total duration of antinociception across all the time points. When spinal rats were tested after morphine administration, there was also an overall significant difference among the groups at 30 min. In this case, the differences were maintained across all time points.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Excitatory amino acids and memory: evidence from research on Alzheimer's disease and behavioral pharmacology.
The excitatory amino acid transmitter (EAA) system is believed to play a crucial role in a variety of physiological processes related to neuronal plasticity. Substantial neurophysiological evidence suggests that, under normal physiological conditions. EAAs may be involved in mechanisms underlying learning and memory. However, overactivity of this system produces excitotoxic damage to neurons which is believed to be an etiological factor in various neurological conditions, such as epilepsy, and stroke-induced impairments. The fact that EAAs have been implicated in both, normal cognitive function and in degenerative neurological conditions suggests that they may contribute to the etiology of Alzheimer's disease (AD), because AD is characterized by memory deficits and specific histopathological signs of neuronal damage. This paper summarizes information regarding 1) the involvement of EAAs in Alzheimer's disease and 2) results from psychopharmacological studies of EAAs in laboratory animal models of learning. Investigations of the pathophysiology of AD indicate that glutamatergic deficits are associated with this syndrome. However, there is controversy concerning the nature of this defect. As a result, it is unclear whether it is a consequence of excitotoxic changes produced by glutamatergic overactivity or result from a decrease in glutamatergic function. Evidence from behavioral studies is consistent with the conclusion that EAAs may be involved in the acquisition of conditioned responses. However, in parallel with the clinical findings, learning impairments have been produced by treatments which either increase or decrease activity within this transmitter system. Therefore, although present results suggest that the EAAs play a role in cognition and in clinical syndromes in which such function is compromised, the specific nature of that role needs to be elucidated by future research.
Alzheimer Disease↗
Evidence for a supraspinal mechanism in the opioid-mediated antinociceptive effect of ketamine.
Systemic ketamine (50 or 160 mg/kg, i.p.) produced an antinociceptive effect in rats on the tail flick test. This effect of ketamine was inhibited by injection of naloxone (27 nmol) into the lateral ventricle. Intrathecal ketamine (3 microns) produced a slight but significant antinociceptive effect on the tail flick test, which was not affected by injection of naloxone (27 nmol) into the lateral ventricle. Antinociception was not produced by injection of ketamine into the lateral ventricle (3 microns) or the rostral ventromedial medulla RVM (30 nmol). The role played by spinal and supraspinal opioid receptors in ketamine-induced antinociception is discussed.
Analgesics↗