PT  - JOURNAL ARTICLE
AU  - Mukae, Takehiro
AU  - Uchida, Hitoshi
AU  - Ueda, Hiroshi
TI  - Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice
AID  - 10.1124/jpet.114.222414
DP  - 2015 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 471--479
VI  - 353
IP  - 3
4099  - http://jpet.aspetjournals.org/content/353/3/471.short
4100  - http://jpet.aspetjournals.org/content/353/3/471.full
SO  - J Pharmacol Exp Ther2015 Jun 01; 353
AB  - 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 μg/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.