Usefulness of Olanzapine as an Adjunct to Opioid Treatment and for the Treatment of Neuropathic Pain

Background 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. Methods 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. Results 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. Conclusion 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.

Download Full-text

The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1999000500005 ◽

1999 ◽

Vol 57 (3B) ◽

pp. 753-760 ◽

Cited By ~ 3

Author(s):

TEREZINHA DE JESUS T. SANTOS ◽

CARLOS M. DE CASTRO-COSTA ◽

SÍLVIO D. A. GIFFONI ◽

FRANKLIN J. C. SANTOS ◽

RODRIGO S. N. RAMOS ◽

...

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Aminobutyric Acid ◽

Thermal Stimulus ◽

Dependent Manner ◽

Gamma Aminobutyric Acid ◽

Analgesic Effects ◽

Nociceptive Stimulus ◽

Dose Dependent

Baclofen (beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Download Full-text

Analysis of the effects of a tricyclic antidepressant on secondary sleep disturbance induced by chronic pain in a preclinical model

PLoS ONE ◽

10.1371/journal.pone.0243325 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243325

Author(s):

Hisakatsu Ito ◽

Yoshinori Takemura ◽

Yuta Aoki ◽

Mizuki Hattori ◽

Hideyo Horikawa ◽

...

Keyword(s):

Chronic Pain ◽

Sleep Disturbance ◽

Thermal Hyperalgesia ◽

Sleep Time ◽

Tricyclic Antidepressant ◽

Preclinical Model ◽

Pain Model ◽

Sleep Quantity ◽

Sleep Condition ◽

Neuropathic Pain Model

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Download Full-text

Locating the Site of Neuropathic Pain In Vivo Using MMP-12-Targeted Magnetic Nanoparticles

Pain Research and Management ◽

10.1155/2019/9394715 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Syeda Fabeha Husain ◽

Raymond W. M. Lam ◽

Tao Hu ◽

Michael W. F. Ng ◽

Z. Q. G. Liau ◽

...

Keyword(s):

Neuropathic Pain ◽

Magnetic Resonance ◽

Intrathecal Injection ◽

Thermal Hyperalgesia ◽

Spinal Nerve ◽

Iron Oxide Nanoparticle ◽

Anatomical Location ◽

Spinal Nerves ◽

Potential Biomarker

Neuropathic pain remains underrecognised and ineffectively treated in chronic pain sufferers. Consequently, their quality of life is considerably reduced, and substantial healthcare costs are incurred. The anatomical location of pain must be identified for definitive diagnosis, but current neuropsychological tools cannot do so. Matrix metalloproteinases (MMP) are thought to maintain peripheral neuroinflammation, and MMP-12 is elevated particularly in such pathological conditions. Magnetic resonance imaging (MRI) of the peripheral nervous system has made headway, owing to its high-contrast resolution and multiplanar features. We sought to improve MRI specificity of neural lesions, by constructing an MMP-12-targeted magnetic iron oxide nanoparticle (IONP). Its in vivo efficiency was evaluated in a rodent model of neuropathic pain, where the left lumbar 5 (L5) spinal nerve was tightly ligated. Spinal nerve ligation (SNL) successfully induced mechanical allodynia, and thermal hyperalgesia, in the left hind paw throughout the study duration. These neuropathy characteristics were absent in animals that underwent sham surgery. MMP-12 upregulation with concomitant macrophage infiltration, demyelination, and elastin fibre loss was observed at the site of ligation. This was not observed in spinal nerves contralateral and ipsilateral to the ligated spinal nerve or uninjured left L5 spinal nerves. The synthesised MMP-12-targeted magnetic IONP was stable and nontoxic in vitro. It was administered onto the left L5 spinal nerve by intrathecal injection, and decreased magnetic resonance (MR) signal was observed at the site of ligation. Histology analysis confirmed the presence of iron in ligated spinal nerves, whereas iron was not detected in uninjured left L5 spinal nerves. Therefore, MMP-12 is a potential biomarker of neuropathic pain. Its detection in vivo, using IONP-enhanced MRI, may be further developed as a tool for neuropathic pain diagnosis and management.

Download Full-text

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1602070113 ◽

2016 ◽

Vol 113 (24) ◽

pp. E3441-E3450 ◽

Cited By ~ 150

Author(s):

Peter M. Grace ◽

Keith A. Strand ◽

Erika L. Galer ◽

Daniel J. Urban ◽

Xiaohui Wang ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Strong Support ◽

Designer Drugs ◽

Male Rats ◽

Receptor Protein ◽

Inflammasome Activation ◽

Opioid Use ◽

Nlrp3 Inflammasomes

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.

Download Full-text

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1516036113 ◽

2016 ◽

Vol 113 (11) ◽

pp. 3036-3041 ◽

Cited By ~ 61

Author(s):

Pooja Singhmar ◽

XiaoJiao Huo ◽

Niels Eijkelkamp ◽

Susana Rojo Berciano ◽

Faiza Baameur ◽

...

Keyword(s):

Chronic Pain ◽

Molecular Mechanism ◽

Inflammatory Pain ◽

Critical Role ◽

Specific Inhibitor ◽

Mechanical Hyperalgesia ◽

Dependent Manner ◽

Phosphorylation Event

cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1−/− mice are protected against inflammatory hyperalgesia in the complete Freund’s adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1−/−, mice. Using sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain.

Download Full-text

Protocatechuic acid as an inhibitor of the JNK/CXCL1/CXCR2 pathway relieves neuropathic pain in CCI rats

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2021.5928 ◽

2021 ◽

Author(s):

Hong-xia Chang ◽

Yue-feng Zhao

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Satellite Cells ◽

Protocatechuic Acid ◽

Thermal Hyperalgesia ◽

Tnf Α ◽

Chemokine Ligand ◽

New Perspective

Emerging evidence has shown that protocatechuic acid (PCA) has antioxidant and anti-inflammatory effects. Evidence suggests that PCA can alleviate the injury of sciatic nerve, while the mechanism of its therapeutic effect on neuralgia remains unknown. Chromium bowel ligation was used in vivo to establish a chronic constriction injury (CCI) rat model to induce sciatic nerve pain. Subsequently, two doses of PCA were used to treat CCI rats. In vitro, 10 ng/mL TNF-α was used to stimulate glial satellite cells derived from the dorsal root ganglia (DRG) L4-L6 of the sciatic nerve to simulate sciatic nerve pain. PCA relieved mechanical allodynia and thermal hyperalgesia in CCI rats. CCK-8 assay revealed that PCA inhibited the proliferation of glial satellite cells induced by TNF-α. Moreover, ELISA demonstrated that PCA could improve the inflammatory response of rats caused by CCI and cells induced by TNF-α. Next, RT-qPCR and Western blot assays showed that PCA blocked the c-Jun N-terminal kinase/the chemokine ligand 1/CXC chemokine receptor 2 (JNK/CXCL1/CXCR2) pathway by inhibiting CXCL1 levels in cells induced by TNF-α and DRG in CCI rats. In conclusion, PCA can alleviate neuropathic pain in CCI rats and improve oxidative stress by inhibiting the JNK/CXCL1/CXCR2 signaling pathway. Thus, these findings provide a new perspective for the treatment of neuropathic pain caused by CCI.

Download Full-text

Nrf2 Activation Attenuates Chronic Constriction Injury-induced Neuropathic Pain via Induction of PGC-1α-mediated Mitochondrial Biogenesis in the Spinal Cord

10.21203/rs.3.rs-723909/v1 ◽

2021 ◽

Author(s):

Jia Sun ◽

Jia-Yan Li ◽

Long-Qing Zhang ◽

Dan-Yang Li ◽

Jia-Yi Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Neuropathic Pain ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Chronic Constriction Injury ◽

Clinical Investigation ◽

Thermal Hyperalgesia ◽

Related Factor ◽

Dependent Manner

Abstract BackgroundNeuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of antioxidant response system. In this study, we investigated whether RTA-408 (a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms.MethodsNeuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von-Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB.ResultsRTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2 dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that PGC-1α activator also exhibited a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the pre-injection of PGC-1α inhibitor.ConclusionsNrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

Download Full-text

Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice

Science Translational Medicine ◽

10.1126/scitranslmed.aay9056 ◽

2021 ◽

Vol 13 (584) ◽

pp. eaay9056 ◽

Cited By ~ 1

Author(s):

Ana M. Moreno ◽

Fernando Alemán ◽

Glaucilene F. Catroli ◽

Matthew Hunt ◽

Michael Hu ◽

...

Keyword(s):

Chronic Pain ◽

Therapeutic Potential ◽

Thermal Hyperalgesia ◽

Structural Similarity ◽

Loss Of Function ◽

Sensory Afferents ◽

Inflammatory State ◽

Epigenetic Repression

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.

Download Full-text

Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression

Journal of Neuroinflammation ◽

10.1186/s12974-019-1696-9 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Shuai Shao ◽

Huan Xia ◽

Min Hu ◽

Chengjuan Chen ◽

Junmin Fu ◽

...

Keyword(s):

Neuropathic Pain ◽

Lateral Roots ◽

Intrathecal Injection ◽

Dependent Manner ◽

Dynorphin A ◽

Diterpenoid Alkaloid ◽

P38 Inhibitor ◽

In Vivo Experiments ◽

Underlying Mechanisms

Abstract Background Isotalatizidine is a representative C19-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain. Methods A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence. Results Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dose-dependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments. Conclusion Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.

Download Full-text

Ameliorative potential of Butea monosperma on chronic constriction injury of sciatic nerve induced neuropathic pain in rats

Anais da Academia Brasileira de Ciências ◽

10.1590/s0001-37652012005000063 ◽

2012 ◽

Vol 84 (4) ◽

pp. 1091-1104 ◽

Cited By ~ 10

Author(s):

Venkata R.K. Thiagarajan ◽

Palanichamy Shanmugam ◽

Uma M. Krishnan ◽

Arunachalam Muthuraman ◽

Nirmal Singh

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Chronic Constriction Injury ◽

Thermal Hyperalgesia ◽

Ethanolic Extract ◽

Thiobarbituric Acid ◽

Positive Control ◽

Nerve Tissue ◽

Dependent Manner ◽

Butea Monosperma

The present study was designed to investigate the ameliorative role of ethanolic extract from leaves of Butea monosperma in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal hyperalgesia, cold chemical allodynia, mechanical hyperalgesia & allodynia in the left hind paw and tail thermal hyperalgesia. Further on, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels were estimated to assess the biochemical changes in the sciatic nerve tissue. Histopathological changes were also observed in the sciatic nerve tissue. Ethanolic extract of Butea monosperma leaves and pregabalin (serving as positive control) were administered for 14 consecutive days starting from the day of surgery. CCI resulted in significant changes in behavioural and biochemical parameters. Pretreatment of Butea monosperma attenuated CCI induced development of behavioural, biochemical and histopathological alterations in a dose dependent manner, which is comparable to that of pregabalin pretreated group. These findings may be attributed to its potential anti-oxidative, neuroprotective and calcium channel modulatory actions of Butea monosperma.

Download Full-text