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.