AS1069562, the (+)-Isomer of Indeloxazine, Exerts Analgesic Effects in a Rat Model of Neuropathic Pain with Unique Characteristics in Spinal Monoamine Turnover

Murai, Norihiko; Aoki, Toshiaki; Tamura, Shinzo; Sekizawa, Tsuyoshi; Kakimoto, Shuichiro; Tsukamoto, Mina; Oe, Tomoya; Enomoto, Ryugo; Hamakawa, Nozomu; Matsuoka, Naoki

doi:10.1124/jpet.113.208686

Cited by 16 publications

(21 citation statements)

References 27 publications

(25 reference statements)

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“…previous findings in rat models of neuropathic pain, which observed that AS1069562 significantly attenuated mechanical allodynia and thermal hyperalgesia in CCI rats (Murai et al, 2014a) and mechanical allodynia in STZ rats (Murai et al, 2014b) at the same dose. Our present finding further suggests that AS1069562 may have potential as a treatment option for patients with chronic muscular pain associated with FM.…”

Section: Discussionsupporting

confidence: 52%

“…Drug concentrations were calculated in terms of free base. AS1069562 and duloxetine were orally administered 1 and 3 h, respectively, before behavioral testing or sampling, as the time point at which the approximately maximum plasma concentration level was achieved (Murai et al, 2014a).…”

Section: Drugsmentioning

confidence: 99%

“…Indeloxazine is a cerebral metabolic enhancer which exerts 5-HT and NE reuptake inhibition (Yamamoto, 1990). AS1069562, the optical (+)-isomer of indeloxazine, exhibits weaker inhibition of cytochrome P450 than indeloxazine and also exerts inhibitory effects against 5-HT and NE reuptake (ShimizuSasamata et al, 1993;Murai et al, 2014a). We recently found that AS1069562 improved both mechanical allodynia and thermal hyperalgesia in a rat model of chronic constriction injury (CCI)-induced neuropathic pain, in contrast, duloxetine only ameliorated mechanical allodynia (Murai et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

“…AS1069562, the optical (+)-isomer of indeloxazine, exhibits weaker inhibition of cytochrome P450 than indeloxazine and also exerts inhibitory effects against 5-HT and NE reuptake (ShimizuSasamata et al, 1993;Murai et al, 2014a). We recently found that AS1069562 improved both mechanical allodynia and thermal hyperalgesia in a rat model of chronic constriction injury (CCI)-induced neuropathic pain, in contrast, duloxetine only ameliorated mechanical allodynia (Murai et al, 2014a). AS1069562 also inhibited both Cfiber-and non-C-fiber-triggered prostaglandin-induced allodynia, while duloxetine inhibited only non-C-fiber-triggered allodynia (Murai et al, 2014c).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats

et al. 2015

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Section: Discussionsupporting

confidence: 52%

Section: Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats

et al. 2015

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“…However, discordant conclusions were drawn from these studies. The study of Murai et al found that duloxetine significantly ameliorated mechanical allodynia at a dose of 30 mg/kg [41] . The study of Bomholt et al showed that duloxetine (30 mg/kg) significantly attenuated thermal hyperalgesia but failed to reduce mechanical allodynia in response to von Frey hair stimuli in CCI rats [42] .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

Zhang

Xue²,

Zhu

et al. 2016

Acta Pharmacol Sin

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Aim:The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo [d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic effects of ammoxetine were assayed using models of acetic acid-and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. Results: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. Conclusion: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.

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

Murai¹,

Tsukamoto²,

Tamura³

et al. 2014

European Journal of Pharmacology

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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.

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AS1069562, the (+)-Isomer of Indeloxazine, Exerts Analgesic Effects in a Rat Model of Neuropathic Pain with Unique Characteristics in Spinal Monoamine Turnover

Cited by 16 publications

References 27 publications

Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats

Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats

Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

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

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