Absence of morphine analgesia and its underlying descending serotonergic activation in an experimental mouse model of fibromyalgia

Nishiyori, Michiko; Nagai, Jun; Nakazawa, Takahiro; Ueda, Hiroshi

doi:10.1016/j.neulet.2010.01.080

Cited by 41 publications

(51 citation statements)

References 40 publications

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“…This model has shown characteristics of a generalized chronic pain phenotype and shares female-predominant sex differences and pharmacotherapeutic features with fibromyalgia patients. Specifically, ICS-induced pain is sensitive to gabapentin and antidepressants (Nishiyori and Ueda, 2008;Nishiyori et al, 2011), but not to morphine (Nishiyori et al, 2010), which is consistent with the clinical evidence of fibromyalgia patients (Clauw, 2014).…”

Section: Introductionsupporting

confidence: 70%

“…We have successfully demonstrated that no significant analgesia is observed by subcutaneous or intracerebroventricular injection of morphine in ICS-treated mice (Nishiyori et al, 2010). As shown in Fig.…”

Section: Resultsmentioning

confidence: 72%

“…1A, paw withdrawal latency against thermal stimuli was approximately 10 seconds in naive animals. We previously showed that ICS markedly reduces the thermal pain threshold to the level of roughly 6 seconds at P1 (Nishiyori et al, 2010). Thermal hyperalgesia lasts for at least 15 days, whereas constant cold stress decreases the threshold to 6 seconds at P1, and hyperalgesia disappears at P5 (Nishiyori and Ueda, 2008;Nishiyori et al, 2010).…”

Section: Resultsmentioning

confidence: 93%

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Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

Mukae

Uchida

Ueda

2015

J Pharmacol Exp Ther

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Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 mg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine.

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Section: Introductionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 93%

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Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

Mukae

Uchida

Ueda

2015

J Pharmacol Exp Ther

Self Cite

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“…In accordance with these findings, neither subcutaneous nor intracerebroventricular injection of morphine has been found to attenuate thermal hyperalgesia in repeated cold stressed mice. Given that serotonin turnover is unlikely to be accelerated by morphine in these animals, a dysfunction in the serotonin-mediated descending inhibitory pathway might explain the absence of morphine analgesia (Nishiyori et al, 2010).…”

Section: Predictive Validitymentioning

confidence: 98%

“…This dysfunction in autonomic control and subsequent development of chronic pain state may be due to changes in certain neurotransmitters, as the repeated cold test has been found to also decrease serotonin and increase noradrenaline and dopamine in the central nervous system (Hata et al, 1987;Hata et al, 1991). The turnover of serotonin in the spinal cord is accordingly reluctant to be activated in mice following exposure to repeated cold stress (Nishiyori et al, 2010).…”

Section: Constructive Validitymentioning

confidence: 99%

Animal Models of Fibromyalgia

Nagakura¹,

Ito²,

Shimizu³

2012

New Insights Into Fibromyalgia

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Fibromyalgia syndrome: metabolic and autophagic processes in intermittent cold stress mice

Oezel

Then

Jung

et al. 2016

Pharmacology Res & Perspec

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Fibromyalgia is characterized by widespread musculoskeletal pain, fatigue, and depression. The aim was to analyze potential mitochondrial dysfunction or autophagy in mice after exposure to intermittent cold stress (ICS). Muscle and liver specimens were obtained from 36 mice. Lactate dehydrogenase (LDH) activity was measured. Microtubule‐associated protein light chain 3 (MAP1LC3B) and glycogen content were determined histologically; muscle ultrastructure by electron microscopy. Mitochondrial‐ and autophagy‐related markers were analyzed by RT‐qPCR and Western blotting. ATP level, cytotoxicity, and caspase 3 activity were measured in murine C2C12 myoblasts after ICS exposure. Coenzyme Q10B (COQ10B) transcript was up‐regulated in limb muscle of ICS mice, whereas its protein content was stable. Cytochrome C oxidase 4 (COX4I1) and LDH activity increased in limb muscle of male ICS mice. Glycogen content was lower in muscle and liver tissue of male ICS mice. Electron micrographs of ICS mice specimens showed mitochondrial damage and autophagic vesicles. A significant up‐regulation of autophagic transcripts of MAP1LC3B and BECLIN 1 (BECN1) was observed. Map1lc3b protein showed an aggregated distribution in ICS mice and SqSTM1/p62 (p62) protein level was stable. Furthermore, ATP level and caspase activity, detected as apoptotic marker, were significantly lowered after ICS exposure in differentiated C2C12 myoblasts. The present study shows that ICS mice are characterized by mitochondrial dysfunction, autophagic processes, and metabolic alterations. Further investigations could dissect autophagy process in the proposed model and link these mechanisms to potential therapeutic options for fibromyalgia.

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Absence of morphine analgesia and its underlying descending serotonergic activation in an experimental mouse model of fibromyalgia

Cited by 41 publications

References 40 publications

Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

Animal Models of Fibromyalgia

Fibromyalgia syndrome: metabolic and autophagic processes in intermittent cold stress mice

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