No abstract

No abstract

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel with high permeability for Ca 2ϩ , primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. 1,2) In addition to chemical ligands such as capsaicin, TRPV1 receptors are also activated by other stimuli such as protons, heat, and some endogenous vanilloids. 3,4) Desensitization of TRPV1 by capsaicin is clinically effective in treating a variety of neuropathic pain conditions. Further, a considerable number of TRPV1 antagonists have shown efficacy in several pain models. 5) Therefore, inhibition of TRPV1 function is an attractive target for treating chronic intractable pain. In contrast, TRPV1 is known to be involved in thermoregulation and antagonism can cause hyperthermia as a side effect. However, recent reports showed that TRPV1 antagonists that can prevent ligand-induced activation without affecting receptor activation by protons have minimal effects on body temperature. 6) We have shown previously that (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) belongs to this group of TRPV1 antagonists, and that it ameliorates neuropathic pain in rats without inducing hyperthermic effects. 7) However, there are few reports regarding the site of action of this type of TRPV1 antagonist in neuropathic pain models, and thus further study is needed.One of the most commonly used model of neuropathic pain is a L5/L6 spinal nerve ligation (SNL) model in rats. Although there have been some investigations of partial sciatic nerve ligation and L5 SNL model using mice, however there have been few studies using L5/L6 SNL model in mice. We previously established the L5/L6 SNL model in mice, which represented a more robust mechanical allodynia and a superior predictive validity than L5 SNL. 8) We also showed that a direct intrathecal (i.t.) injection technique could be applied in this model. This method in unanesthetized mice allows reliable, rapid, and easy evaluation of drug effects without complicated surgery. Here, we assess the pharmacokinetics and in vivo TRPV1 antagonist activity of AS1928370 in mice, and evaluate the analgesic effects of orally and intrathecally administered AS1928370 to investigate the action site of TRPV1 antagonists in an SNL model. In addition, we examined the effects of AS1928370 on locomotion to characterize the side effect profile of this drug in mice. MATERIALS AND METHODSMaterials (R)-N-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) was synthesized at Astellas Pharma Inc. (Tsukuba, Japan). A monohydrochloride salt of AS1928370 was used as AS1928370. AS1928370 was suspended in 0.5% methylcellulose aqueous solution and administered orally in a volume of 10 ml/kg, or dissolved in 20% 2-hydroxypropyl-b-cyclodextrin and administered intrathecally (i.t.) in a volume of 5 ml in unanesthetized mice according to the method established by Hylden a...

AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (1)-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.

No abstract

ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11β-HSD1. The effects of ASP3662 suggest that selective inhibition of 11β-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.

No 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.