clozapine and Neuralgia

Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

Topics: Animals; Chronic Pain; Clozapine; Inflammasomes; Interleukin-1beta; Male; Microglia; Morphine; Neuralgia; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn

Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia.. In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens.. The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well.. Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Topics: Animals; Clozapine; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Exercise Test; Exercise Therapy; Hyperalgesia; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuralgia; Nucleus Accumbens; Pain Measurement; Pain Threshold; Phosphopyruvate Hydratase; Receptors, G-Protein-Coupled; Serotonin Antagonists; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The use of opioids for pain management is often associated with nausea and vomiting. Although conventional antipsychotics are often used to counter emesis, they can be associated with extrapyramidal symptoms. However, chronic pain can induce sleep disturbance. The authors investigated the effects of the atypical antipsychotic olanzapine on morphine-induced emesis and the sleep dysregulation associated with chronic pain.. A receptor binding assay was performed using mouse whole brain tissue. The emetic response in ferrets was evaluated by counting retching and vomiting behaviors. Catalepsy in mice was evaluated by placing both of their forepaws over a horizontal bar. Released dopamine was measured by an in vivo microdialysis study. Sleep disturbance in mice in a neuropathic pain-like state was assayed by electroencephalogram and electromyogram recordings.. Olanzapine showed high affinity for muscarinic M1 receptor in brain tissue. Olanzapine decreased morphine-induced nausea and vomiting in a dose-dependent manner. However, olanzapine at a dose that had an antiemetic effect (0.03 mg/kg) did not induce catalepsy or hyperglycemia. In addition, olanzapine at this dose had no effect on the morphine-induced release of dopamine or inhibition of gastrointestinal transit. Finally, olanzapine inhibited thermal hyperalgesia and completely alleviated the sleep disturbance induced by sciatic nerve ligation.. These findings suggest that olanzapine may be useful for the treatment of morphine-induced emesis and as an adjunct for the treatment of neuropathic pain associated with sleep disturbance.

Topics: Analgesics, Opioid; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Brain Chemistry; Catalepsy; Clozapine; Dopamine; Drug Therapy, Combination; Electroencephalography; Electromyography; Gastrointestinal Transit; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Microdialysis; Morphine; Neuralgia; Olanzapine; Pain Management; Receptors, Serotonin; Sciatica; Sleep Wake Disorders; Vomiting

Patients with schizophrenia have been shown to display decreased sensitivity to pain, which can severely compound the impact of injuries and illnesses. Alterations in the sensory and affective systems of pain processing have been proposed as mechanisms, but the unique contribution of each of these systems has not been elucidated. The aim of this study was to investigate these two components of pain using the NMDA receptor antagonist, phencyclidine (PCP), an established animal model of schizophrenia. Animals underwent L5 spinal nerve ligation surgery in order to provoke a condition of ongoing pain responding, followed by treatment with 2.58 mg/kg of PCP, or saline, and 20 mg/kg of the atypical antipsychotic clozapine, or vehicle, in a block design. Responses to mechanical stimuli were assessed to determine changes in sensory processing, and affective pain processing was examined with the place escape avoidance paradigm. The results showed animals receiving PCP exhibited decreased sensitivity to mechanical stimulation and unaltered behavior in the avoidance paradigm. These findings corroborate and strengthen the human literature investigating schizophrenia and alterations in pain perception. More importantly, the differential findings between the tests of sensory and affective pain processing provide a novel means of understanding schizophrenia-related pain insensitivity.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Clozapine; Disease Models, Animal; Escape Reaction; Excitatory Amino Acid Antagonists; Ligation; Male; Neuralgia; Pain Perception; Phencyclidine; Physical Stimulation; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Spinal Nerves; Stress, Mechanical

Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.

Topics: Analgesics; Animals; Benzimidazoles; Drug Design; Drug Evaluation, Preclinical; Humans; Microsomes, Liver; Neuralgia; Nociceptin Receptor; Pyrroles; Rats; Receptors, Opioid; Structure-Activity Relationship