Abstract
Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)–induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2 and postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4 to 5 days after the cessation of treatments. The repeated mirtazapine treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of small interfering RNA (siRNA) adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracerebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that mirtazapine could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions.
SIGNIFICANCE STATEMENT This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)–induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the antihyperalgesia, whereas other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS model.
Footnotes
- Received February 25, 2020.
- Accepted July 13, 2020.
↵1 Current affiliation: RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
↵2 Current affiliation: Department of Molecular Pharmacology, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan.
↵3 Current affiliation: Department of Cellular Neuropathology, Brain Research Institute, Niigata University, Niigata, Japan.
This work was supported in part by Grants-in-Aid for the Platform for Drug Discovery, Informatics, and Structural Life Science [16am0101012j0005 to H.U.] from the Japan Agency for Medical Research and Development (AMED), Japan, and from KAKENHI JP17H01586 (to H.U.) and JP26253077 (to H.U.) from Japan Society for the Promotion of Science (JSPS).
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- Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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