Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

Background and objectivesKetamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.MethodsMice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia.ResultsIn all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1–24hours compared with saline (F=121.6, p<0.0001), and three daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F=33.4, p=0.0002). In the CRPS1 model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F=116.1, p<0.0001). In the postoperative pain model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F=60.6, p<0.0001).ConclusionsThis study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.

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Influences of Suvorexant and Mirtazapine on Chronic Pain-related Sleep Disorder in Neuropathic Pain Model Mice

10.21203/rs.3.rs-383177/v1 ◽

2021 ◽

Author(s):

Hisakatsu Ito ◽

Hiroshi Tusneki ◽

Toshiyasu Sasaoka ◽

Naoki Toyooka ◽

Mitsuaki Yamazaki

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Sleep Disorders ◽

Sleep Onset ◽

Voluntary Activity ◽

Pain Model ◽

Neuropathic Pain Model ◽

Pain State ◽

Serotonergic Antidepressant

Abstract Chronic pain and sleep disorders are independently associated with a reduction in the quality of life. They can be both a cause and consequence of each other; therefore, they should be treated simultaneously. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related sleep disorders in a preclinical neuropathic pain mouse model, which was produced by partial sciatic nerve ligation. We calculated the quantity, duration, and depth of sleep by analyzing the electroencephalogram. Voluntary activity was also evaluated by counting the number of wheel rotations with special cages. Daily administration of suvorexant and mirtazapine normalized the reduced rapid eye movement (REM) and non-REM sleep and improved the fragmented sleep, further regaining the depth of sleep at sleep onset in the chronic pain state. Suvorexant decreased voluntary activity, which was prolonged after the end of administration; however, mirtazapine did not decrease it. Both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

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Effect of preoperative gabapentin on pain intensity and development of chronic pain after carpal tunnel syndrome surgical treatment in women: randomized, double-blind, placebo-controlled study

Sao Paulo Medical Journal ◽

10.1590/1516-3180.2015.00980710 ◽

2016 ◽

Vol 134 (4) ◽

pp. 285-291 ◽

Cited By ~ 2

Author(s):

Eduardo Jun Sadatsune ◽

Plínio da Cunha Leal ◽

Rachel Jorge Dino Cossetti ◽

Rioko Kimiko Sakata

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Surgical Treatment ◽

Postoperative Pain ◽

Carpal Tunnel Syndrome ◽

Carpal Tunnel ◽

Postoperative Analgesia ◽

Pain Syndrome ◽

Double Blind ◽

Tunnel Syndrome

ABSTRACT CONTEXT AND OBJECTIVES: Effective postoperative analgesia is important for reducing the incidence of chronic pain. This study evaluated the effect of preoperative gabapentin on postoperative analgesia and the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgical treatment. DESIGN AND SETTINGS: Randomized, double-blind controlled trial, Federal University of São Paulo Pain Clinic. METHODS: Forty patients aged 18 years or over were randomized into two groups: Gabapentin Group received 600 mg of gabapentin preoperatively, one hour prior to surgery, and Control Group received placebo. All the patients received intravenous regional anesthesia comprising 1% lidocaine. Midazolam was used for sedation if needed. Paracetamol was administered for postoperative analgesia as needed. Codeine was used additionally if the paracetamol was insufficient. The following were evaluated: postoperative pain intensity (over a six-month period), incidence of postoperative neuropathic pain (over a six-month period), need for intraoperative sedation, and use of postoperative paracetamol and codeine. The presence of neuropathic pain was established using the DN4 (Douleur Neuropathique 4) questionnaire. Complex regional pain syndrome was diagnosed using the Budapest questionnaire. RESULTS: No differences in the need for sedation, control over postoperative pain or incidence of chronic pain syndromes (neuropathic or complex regional pain syndrome) were observed. No differences in postoperative paracetamol and codeine consumption were observed. CONCLUSIONS: Preoperative gabapentin (600 mg) did not improve postoperative pain control, and did not reduce the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgery.

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Rufinamide alleviates mechanical allodynia in a mouse neuropathic pain model

European Journal of Anaesthesiology ◽

10.1097/00003643-201106001-00622 ◽

2011 ◽

Vol 28 ◽

pp. 193

Author(s):

M. R. Suter ◽

G. Kirschmann ◽

H. Abriel ◽

I. Decosterd

Keyword(s):

Neuropathic Pain ◽

Mechanical Allodynia ◽

Pain Model ◽

Neuropathic Pain Model

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Minocycline attenuates mechanical allodynia and expression of spinal NMDA receptor 1 subunit in rat neuropathic pain model

Journal of Physiology and Biochemistry ◽

10.1007/s13105-012-0217-4 ◽

2012 ◽

Vol 69 (3) ◽

pp. 349-357 ◽

Cited By ~ 15

Author(s):

Shaofeng Pu ◽

Yongming Xu ◽

Dongping Du ◽

Meirong Yang ◽

Xin Zhang ◽

...

Keyword(s):

Neuropathic Pain ◽

Nmda Receptor ◽

Mechanical Allodynia ◽

Pain Model ◽

Neuropathic Pain Model

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A streptozotocin-induced diabetic neuropathic pain model for static or dynamic mechanical allodynia and vulvodynia: validation using topical and systemic gabapentin

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-015-1145-y ◽

2015 ◽

Vol 388 (11) ◽

pp. 1129-1140 ◽

Cited By ~ 22

Author(s):

Gowhar Ali ◽

Fazal Subhan ◽

Muzaffar Abbas ◽

Jehan Zeb ◽

Muhammad Shahid ◽

...

Keyword(s):

Neuropathic Pain ◽

Mechanical Allodynia ◽

Diabetic Neuropathic Pain ◽

Pain Model ◽

Dynamic Mechanical ◽

Neuropathic Pain Model

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Spinal Microglial Expression and Mechanical Hypersensitivity in a Postoperative Pain Model: Comparison with a Neuropathic Pain Model

Anesthesiology ◽

10.1097/aln.0b013e3181b05f42 ◽

2009 ◽

Vol 111 (3) ◽

pp. 640-648 ◽

Cited By ~ 33

Author(s):

Naomi Ito ◽

Hideaki Obata ◽

Shigeru Saito

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Postoperative Pain ◽

Model Comparison ◽

Kinase Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Sprague Dawley ◽

Pain Model ◽

Mechanical Hypersensitivity ◽

Neuropathic Pain Model

Background Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model. Methods Male Sprague-Dawley rats underwent either unilateral plantar hind paw incision (postoperative pain model) or L5 spinal nerve transection (neuropathic pain model), and the development of mechanical hypersensitivity was assessed using von Frey filaments. The microglial inhibitor minocycline was intraperitoneally administered daily for either 3 or 7 days. Spinal microglial activation was evaluated by OX42 immunohistochemistry. We also tested the effect of intrathecal administration of a p38 mitogen-activated protein kinase inhibitor, SB203580. Results In the postoperative pain model, minocycline did not suppress mechanical hypersensitivity, but did inhibit an increase in spinal OX42 expression. In contrast, in the neuropathic pain model, minocycline reduced mechanical hypersensitivity in a dose-related manner and inhibited spinal OX42 expression. SB203580 attenuated hypersensitivity in the neuropathic pain model, but not in the postoperative pain model. Conclusions The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.

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