Antinociceptive effects of AS1069562, the (+)-isomer of indeloxazine, on spinal hypersensitivity induced by intrathecal injection of prostaglandin in mice: Comparison with duloxetine and amitriptyline

Abstract

The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. Allodynia induced by PGF2α but not by PGE2 was suppressed by desensitization of C-fibers with systemic pretreatment with resiniferatoxin. C-fiber hyperexcitability might therefore play a role in allodynia induced by PGF2α but not PGE2. In the PGE2-induced allodynia model, AS1069562 and duloxetine significantly suppressed allodynia, whereas amitriptyline did not. In the PGF2α-induced allodynia model, AS1069562 and amitriptyline significantly ameliorated allodynia, whereas duloxetine did not. To demonstrate the broad effects of AS1069562 compared to duloxetine, additional studies were conducted to elucidate other target mechanisms of AS1069562 beyond 5-HT and norepinephrine reuptake inhibition. AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α-induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)-WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors.

Glycine receptors expression in rat spinal cord and dorsal root ganglion in prostaglandin E2 intrathecal injection models

“…The prostaglandin E2 (EMD Millipore Corp., MA, USA) was dissolved in 99.9% ethanol at a concentration of 1 mg/ml. Different PGE2 dose intrathecal injection has been reported in mice [ 5 , 6 ]. After converting the dose from mouse to rat [ 7 ], we used a concentration of PGE2 intrathecal injection of 625 ng/25 ul (equals to 25 mg/ml).…”

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…A similar scaffold, with an additional therapeutic target (pain), is that of the (+)enantiomer ( 82 ) of the antiepileptic drug Indeloxazine, with 5‐HT as well as norepinephrine reuptake inhibitory activity (IC 50 = 0.83 μM and IC 50 = 6.8 μM, respectively) . It was also effective (in rats) in improving nociception, possibly by its effects on spinal 5‐HT 1A and 5‐HT 3 receptors.…”

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain

“…We recently reported that repeated dosing of AS1069562 has a curative-like analgesic effect even after a 1-week drug discontinuation in a rat model of streptozotocin-induced diabetic neuropathy with the restoration of growth factors. 21 In addition, agonistic action of the 5-HT 1A receptor is involved in the analgesic effect of AS1069562 on allodynia in mice, 20 and high-efficacy 5-HT 1A receptor activation for 56 days has been reported to cause a curative-like effect on allodynia in rats with spinal cord injury. 22 Mechanisms such as restoration of growth factors and activation of 5-HT 1A receptor might contribute to the more persistent analgesic effect of AS1069562 than duloxetine, the details of which need to be clarified.…”

“…18,19 We recently found that AS1069562 improved various types of neuropathic pain-related behaviors in a rat model of chronic constriction injury (CCI)-induced neuropathic pain, 19 and AS1069562 inhibited both Cfiber-and non-C-fiber-triggered prostaglandin-induced allodynia. 20 Further, repeated dosing of AS1069562 induced a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy. 21 However, the analgesic effects of AS1069562 on nociceptive pain have not been fully elucidated.…”