clozapine and Pain

Topics: Aged; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Diagnosis, Differential; Female; Humans; Metabolic Syndrome; Middle Aged; Olanzapine; Pain; Patient Compliance; Peripheral Nervous System Diseases; Piperazines; Quinolones; Schizophrenia, Paranoid; Skin Diseases, Parasitic; Sleep Wake Disorders

Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep-wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin-DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin-DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery.

Topics: Anesthesia Recovery Period; Anesthetics, Inhalation; Animals; Clozapine; Dependovirus; Electroencephalography; Gene Expression Regulation; Genetic Vectors; Hot Temperature; Hypothalamus; Isoflurane; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Orexin Receptors; Orexins; Pain; Pain Measurement; Patch-Clamp Techniques; Proto-Oncogene Proteins c-fos; Serotonin Antagonists; Stereotaxic Techniques

Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.

Topics: Animals; Cells, Cultured; Channelrhodopsins; Clozapine; Combined Modality Therapy; Disease Models, Animal; Low-Level Light Therapy; Mice; Nociception; Optogenetics; Pain

The gate control theory (GCT) of pain proposes that pain- and touch-sensing neurons antagonize each other through spinal cord dorsal horn (DH) gating neurons. However, the exact neural circuits underlying the GCT remain largely elusive. Here, we identified a new population of deep layer DH (dDH) inhibitory interneurons that express the receptor tyrosine kinase Ret neonatally. These early RET+ dDH neurons receive excitatory as well as polysynaptic inhibitory inputs from touch- and/or pain-sensing afferents. In addition, they negatively regulate DH pain and touch pathways through both pre- and postsynaptic inhibition. Finally, specific ablation of early RET+ dDH neurons increases basal and chronic pain, whereas their acute activation reduces basal pain perception and relieves inflammatory and neuropathic pain. Taken together, our findings uncover a novel spinal circuit that mediates crosstalk between touch and pain pathways and suggest that some early RET+ dDH neurons could function as pain "gating" neurons.

Topics: Animals; Clozapine; Female; Interneurons; Male; Mice; Mice, Transgenic; Neural Inhibition; Neurons; Pain; Pain Measurement; Proto-Oncogene Proteins c-ret; Spinal Cord; Spinal Cord Dorsal Horn; Touch

The first of the atypical antipsychotics introduced in the 1970s, clozapine remains the most efficacious neuroleptic to this day. However, serious and potentially fatal side effects have necessitated careful regular monitoring among prescribing clinicians. Some adverse effects (e.g. ischaemic bowel) remain under recognized, while newly identified adverse effects continue to be described in the literature.. In this report, we describe a healthy 43-year old Caucasian male who experienced onset of a full body deep burning pain several months after the onset of treatment with clozapine. The pain worsened over time, ceased with cessation of treatment, and returned soon after the patient was rechallenged.. We describe an unusual adverse effect from clozapine treatment that has not been described elsewhere to our knowledge. We present the time course of the pain symptom, relationship to dose, associated laboratory results, and ultimately how it was dealt with and how it improved for the benefit of clinicians who may encounter it in the future.

Topics: Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Humans; Male; Pain; Psychotic Disorders

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Creatine Kinase; Depressive Disorder, Major; Dibenzothiazepines; Humans; Male; Mianserin; Mirtazapine; Olanzapine; Pain; Psychotic Disorders; Quetiapine Fumarate

The tricyclic antidepressants amitriptyline (CAS 549-18-8), amitriptylinoxide (CAS 4317-14-0) and doxepine (CAS 1229-29-4) as well as the atypical neuroleptic clozapine (CAS 5786-21-0)--all of them substances with well-established clinical efficacy--were investigated in order to elucidate their effect on N-methyl-D-aspartate (NMDA) receptor-mediated events. Modulation of NMDA receptor function was studied using the model of NMDA-evoked [3H]-acetylcholine ([3H]-ACh) release in slices of rat caudatoputamen. All substances reduced [3H]-ACh release in a concentration dependent manner. Significant inhibition occurred in the low micromolar range with the exception of amitriptylinoxide which was less potent in vitro (amitriptylinoxide is not being metabolized in vitro). Amitriptyline and clozapine at 10 mumol/l both decreased the maximum effect of NMDA by around 17%, but left its EC50 unchanged. This suggests a "classical" non-competitive antagonism and excludes an uncompetitive or "use-dependent" antagonism. Considering the important role of NMDA receptor-mediated effects in spinal nociception the analgesic properties of tricyclic antidepressants may partly be explained by their inhibitory action on spinal NMDA receptors, in addition to their enhancement of monoaminergic transmissions in the dorsal horn.

Topics: Acetylcholine; Algorithms; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Caudate Nucleus; Chronic Disease; Clozapine; Doxepin; Excitatory Amino Acid Agonists; Male; N-Methylaspartate; Pain; Putamen; Rats; Rats, Wistar

The case of a patient with sleep-related painful erections is described. Insomnia and a slight depressive syndrome occurred along with a long history of this disorder. No physical abnormality was found. At a baseline recording of sleep electroencephalography (EEG) and nocturnal penile tumescence (NPT), a disturbed sleep pattern and impaired NPT were recorded. Attempts to treat the disorder with diazepam, amitriptyline, trimipramine, and biperidene did not prompt a stable improvement of the disorder, but a dosage of 25 mg clozapine was sufficient to achieve normalized sleep architecture, remission of the depressive symptomatology, and normalization of NPT. It is likely that marked sedation is the mode of action of clozapine.

Topics: Administration, Oral; Adult; Clozapine; Dibenzazepines; Electroencephalography; Evoked Potentials; Humans; Male; Pain; Penile Erection; Sleep Initiation and Maintenance Disorders; Sleep Stages