The Atypical Neuroleptics Clozapine and Olanzapine Differ Regarding Their Antinociceptive Mechanisms and Potency

Schreiber, Shaul; Getslev, V.; Backer, Maria M; Weizman, Ronit; Pick, Chaim G.

doi:10.1016/s0091-3057(99)00107-0

Cited by 63 publications

(42 citation statements)

References 17 publications

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“…Rank ordering of SGAs' binding affinities argues against antagonism of a single receptor as a sufficient cause for SGA-induced weight gain (Richelson, 1999;Richelson and Souder, 2000). It is possible that simultaneous blockade of H 1 , 5-HT 2 , D 2 , and acetylcholine receptors plays a synergistic role in increased appetite and food intake (Richelson, 1999;Richelson and Souder, 2000) Chemistry Opioidergic activity m (Schreiber et al, 1997;Schreiber et al, 1999;Weizman et al, 2003;O'Malley et al, 1999;Kochhar et al, 2002;Palenzona et al, 2004) SGAs may worsen opioid-mediated food hedonics BDNF m In hippocampus and in PFC (Bai et al, 2003;Angelucci et al, 2005;Luo et al, 2004) Clinical significance of these changes observed in preclinical studies is unknown Orexin K Preclinical study: m in activity in LH K Clinical study: no effect in CSF (Dalal et al, 2003) The preclinical study revealed high degree of specificity for the LH site of orexin effects; such neuroanatomic precision was unattainable with CSF sampling employed in the clinical study…”

Section: Effects Of Sgas On Food Intakementioning

confidence: 99%

“…These include clinical presentation of olanzapine overdose, which is indistinguishable from opioid intoxication (O'Malley et al, 1999;Kochhar et al, 2002;Palenzona et al, 2004) and analgesic/antinociceptive properties of clozapine, olanzapine, and rispiridone observed in both human (Kiser et al, 2001;Silberstein et al, 2002;Fe-Bornstein et al, 2002;Khojainova et al, 2002;Gorski and Willis, 2003) and rodent (Schreiber et al, 1997(Schreiber et al, , 1999Weizman et al, 2003) models and ascribed to the opioid mechanisms (Schreiber et al, 1997(Schreiber et al, , 1999Weizman et al, 2003). Taken together, these results suggest that SGAs are likely to have positive impact on the incentive/ motivational reward aspects (including drive to procure food), but at the cost of worsened, or at least not improved opioid-mediated hedonic capacity.…”

Section: Opioid Antagonists May Improve Hedonic Deficits In Patients mentioning

confidence: 99%

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Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

131

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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Section: Effects Of Sgas On Food Intakementioning

confidence: 99%

Section: Opioid Antagonists May Improve Hedonic Deficits In Patients mentioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

131

142

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“…Chronic administration of clozapine to rats and mice increased proenkephalin mRNA expression in striatum and nucleus accumbens, dynorphin levels in substantia nigra (Angulo et al, 1990), and the density of brain m-and d-opioid receptors (Zang et al, 1995). In mice, the acute injection of clozapine was found to produce analgesia using the tail-flick test and this effect was antagonized by naloxone and selective m-and k-opioid receptor antagonists (Schreiber et al, 1999). Studies in vitro have shown that clozapine inhibited [ 3 H]Met-enkephalin binding to synaptosomeenriched fractions of rat whole brain and hippocampus with a micromolar potency (Somoza et al, 1981).…”

Section: Introductionmentioning

confidence: 98%

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

Onali

Olianas

2006

Neuropsychopharmacol

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The present study examined the effects of N-desmethylclozapine (NDMC), a biologically active metabolite of the atypical antipsychotic clozapine, at cloned human opioid receptors stably expressed in Chinese hamster ovary (CHO) cells and at native opioid receptors present in NG108-15 cells and rat brain. In CHO cells expressing the d-opioid receptor (CHO/DOR), NDMC behaved as a full agonist both in stimulating [ 35 S]GTPgS binding (pEC 50 ¼ 7.24) and in inhibiting cyclic AMP formation (pEC 50 ¼ 6.40). NDMC inhibited [ 3 H]naltrindole binding to CHO/DOR membranes with competition curves that were modulated by guanine nucleotides in an agonistlike manner. Determination of intrinsic efficacies by taking into consideration both the maximal [ 35 S]GTPgS binding stimulation and the extent of receptor occupancy at which half-maximal effect occurred indicated that NDMC had an efficacy value equal to 82% of that of the full d-opioid receptor agonist DPDPE, whereas clozapine and the other clozapine metabolite clozapine N-oxide displayed much lower levels of agonist efficacy. NDMC exhibited poor agonist activity and lower affinity at the k-opioid receptor and was inactive at m-opioid and NOP receptors. In NG108-15 cells, NDMC inhibited cyclic AMP formation and stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 by activating the endogenously expressed d-opioid receptor. Moreover, in membranes of different brain regions, NDMC stimulated [ 35 S]GTPgS binding and regulated adenylyl cyclase activity and the effects were potently antagonized by naltrindole. These data demonstrate for the first time that NDMC acts as a selective and efficacious d-opioid receptor agonist and suggest that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine. Neuropsychopharmacology (2007) 32, 773-785.

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“…Thus, the possible use of these agents in treatment of pain is an issue which can be given a trial. There are studies showing augmenting effects of neuroleptic agents like risperidone (Schreiber et al., 1997) 4 and also with atypical neuroleptic drugs clozapine and olanzapine (Schreiber et al, 1999) 5 on opioid induced anti-nociception. Amisulpride is an atypical antipsychotic agent, chemically a substituted benzamide.…”

Section: Introductionmentioning

confidence: 99%

“…Since amisulpride involves dopamine D3 receptor blockade, it is hypothesized that it would exert an antinociceptive effect. Furthermore, in previous studies it was found that different dopamine receptor subtypes mediate anti-nociception by different interactions with the opioid system (Schreiber et al, 1997(Schreiber et al, , 1999 4,5 , thus assessing the anti-nociceptive properties of a drug that interacts both with dopamine D2 and D3 receptors (amisulpride) may shed some light on the different effects of dopamine D2 and D3 receptor subtypes on opioid regulation. It was found that the sensitivity of amisulpride-induced anti-nociception is mediated through selective involvement of all three opioid receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of Analgesic Effect of Amisulpride With Tramadol in Mice

Bhavika¹,

Begum²,

Swathi³

et al. 2015

J Pharm Sci Innov

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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. In view of the considerable side effects produced by the available analgesics, the search for a newer analgesic continues. The aim of this study is to anti nociceptive effects of various neuroleptics in animal models of pain have been described. The aim of our present study is to evaluate the analgesic activity of Amisulpride, an atypical antipsychotic in comparison with Tramadol, which is a synthetic opioid analgesic. The analgesic effect of Amisulpride was evaluated using Eddy's hot plate. The drugs were administered sub-cutaneously. In this test the reaction times i.e., the latency periods in the animals were recorded in all the three groups (control, standard and test groups) at 30 min, 60 min and 90 min time interval after drug administration. Each group contains 6 animals. The increase in reaction time in response to a drug denotes analgesic effect of the drug. The reaction times in the test group were compared with standard and control. Results were analyzed by ANOVA followed by post hoc Dunnett's test. According to Dunnett's test, the p value was very significant in Control vs test group at 90 min, which implies that Amisulpride (44 mg/kg) has significant analgesic effect at 90 min time interval after drug administration. P values were very significant at 30 min and 60 min and not significant at 90 min in Standard group versus Test group, which implies that the test drug (Amisulpride) has analgesic effect comparable to that of standard drug (Tramadol) at 90 min. This study suggests that Amisulpride has significant analgesic effect at 90 min. The analgesic effect of Amisulpride (44 mg/kg) is comparable to that of standard drug Tramadol (20 mg/kg) at 90 min.

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The Atypical Neuroleptics Clozapine and Olanzapine Differ Regarding Their Antinociceptive Mechanisms and Potency

Cited by 63 publications

References 17 publications

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

Comparative Study of Analgesic Effect of Amisulpride With Tramadol in Mice

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