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J Pharmacol Exp Ther. 2014 Mar;348(3):372-82. doi: 10.1124/jpet.113.208686. Epub 2013 Dec 12.

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in a rat model of neuropathic pain with unique characteristics in spinal monoamine turnover.

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1
Pharmacology Research Laboratories (N.Mu., T.A., S.T., T.S., S.K., M.T., T.O., R.E., N.Ma.) and Analysis & Pharmacokinetics Research Laboratories (N.H.), Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.

Abstract

AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (+)-isomer of indeloxazine, which had been used clinically for the treatment of cerebrovascular diseases with multiple pharmacological actions, including serotonin (5-HT) and norepinephrine (NE) reuptake inhibition. Here we investigated the analgesic effects of AS1069562 in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and the spinal monoamine turnover. These effects were compared with those of the antidepressants duloxetine and amitriptyline. AS1069562 significantly elevated extracellular 5-HT and NE levels in the rat spinal dorsal horn, although its 5-HT and NE reuptake inhibition was much weaker than that of duloxetine in vitro. In addition, AS1069562 increased the ratio of the contents of both 5-HT and NE to their metabolites in rat spinal cord, whereas duloxetine slightly increased only the ratio of the content of 5-HT to its metabolite. In CCI rats, AS1069562 and duloxetine significantly ameliorated mechanical allodynia, whereas amitriptyline did not. AS1069562 and amitriptyline significantly ameliorated thermal hyperalgesia, and duloxetine tended to ameliorate it. Furthermore, AS1069562, duloxetine, and amitriptyline significantly improved spontaneous pain-associated behavior. In a gastric emptying study, AS1069562 affected gastric emptying at the same dose that exerted analgesia in CCI rats. On the other hand, duloxetine and amitriptyline significantly reduced gastric emptying at lower doses than those that exerted analgesic effects. These results indicate that AS1069562 broadly improved various types of neuropathic pain-related behavior in CCI rats with unique characteristics in spinal monoamine turnover, suggesting that AS1069562 may have potential as a treatment option for patients with neuropathic pain, with a different profile from currently available antidepressants.

PMID:
24338505
DOI:
10.1124/jpet.113.208686
[Indexed for MEDLINE]
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