Pharmacological characterization and gene expression profiling of an L5/L6 spinal nerve ligation model for neuropathic pain in mice

Kiso, Tetsuo; Watabiki, Tomonari; Tsukamoto, Mina; Okabe, Masaru; Kagami, Mitsuhiro; Nishimura, Kazumi; Aoki, Toshiaki; Matsuoka, Naoki

doi:10.1016/j.neuroscience.2008.02.031

Cited by 51 publications

(37 citation statements)

References 53 publications

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“…In our results, gabapentin is effective for mechanical allodynia but very high doses (100 mg/kg p.o.) were needed to alleviate it, as reported previously (Kiso et al, 2008). Under this experimental condition, the antiallodynic effect of MGM-16 is approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice.…”

Section: Discussionsupporting

confidence: 81%

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Matsumoto

Narita

Muramatsu

et al. 2013

J Pharmacol Exp Ther

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(E)-Methyl 2-((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1, 2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (7-hydroxymitragynine), a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7-Hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through m-opioid receptors. In this study, we developed dual-acting m-and d-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in in vitro and in vivo assays. MGM-16 exhibited a high affinity for m-and d-opioid receptors, with K i values of 2.1 and 7.0 nM, respectively. MGM-16 showed m-and d-opioid full agonistic effects in a guanosine 59-O-(3-[ 35 S]thiotriphosphate) binding assay and in a functional test using electrically elicited guinea pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the m-selective antagonist b-funaltrexamine hydrochloride (b-FNA) and by the d-selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by b-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain.

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Section: Discussionsupporting

confidence: 81%

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Matsumoto

Narita

Muramatsu

et al. 2013

J Pharmacol Exp Ther

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“…14,15) We previously showed that clinically used antineuropathic agents such as pregabalin and duloxetine were effective in SNL mice. 8) In the present study, the analgesic efficacy of AS1928370 was similar to that of these anti-neuropathic agents. Notably, the effective dose in SNL mice was lower than that in the capsaicin and hot-plate tests.…”

Section: Discussionsupporting

confidence: 76%

“…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.…”

mentioning

confidence: 71%

“…Current existing drugs for neuropathic pain, such as pregabalin and morphine, frequently cause central side-effects in human patients, and we previously reported that these drugs modulate locomotor activities at similar doses to those required for analgesia in mice. 8) These findings suggest that AS1928370 is less likely to cause CNS-related side effects. In addition, we previously showed that AS1928370 belongs to the group of TRPV1 antagonists which have minimal potency for inducing hyperthermia.…”

Section: Discussionmentioning

confidence: 95%

“…8) In brief, the left L5 and L6 spinal nerves were tightly ligated with 6-0 silk thread, and the wound was sutured under pentobarbital sodium anesthesia. Mice that exhibited a motor disorder in the left foot were excluded from the subsequent examination.…”

Section: Methodsmentioning

confidence: 99%

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Intrathecal Administration of AS1928370, a Transient Receptor Potential Vanilloid 1 Antagonist, Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain

Watabiki

Kiso

Tsukamoto

et al. 2011

Biological & Pharmaceutical Bulletin

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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...

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Pregabalin Alters Nociceptive Behavior and Expression Level of P2X3 Receptor in the Spinal Dorsal Horn in a Rat Model Induced by Chronic Compression of the Dorsal Root Ganglion

Zhang

et al. 2013

The Anatomical Record

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P2X3 receptors are present in the spinal dorsal horn (SDH) and play an essential role in the regulation of nociception and pain. Pregabalin (PGB) has been used as a new antiepileptic drug in the treatment of neuropathic pain. However, it is unclear whether PGB-induced analgesia was associated with the P2X3 receptor in SDH. Here, rats were randomly divided into four groups (n 5 12 per group), including 2 sham operation groups, which was treated by normal saline (Sham 1 NS group) or PGB (Sham 1 PGB group), other 2 groups with chronic compression of the dorsal root ganglion, a normal saline-treated CCD group (CCD1NS group), and a PGB-treated CCD group (CCD 1 PGB group). A rat model of neuropathic pain was used by compressing the right L4 and L5 dorsal root ganglia. Each group was evaluated using the mechanical withdrawal threshold (MWT). The mRNA and protein levels of the P2X3 receptor in the ipsilateral SDH were measured by RT-PCR, western blot, and immunofluorescence on 14 day after CCD operation. CCD rats showed the highest mechanical hyperalgesia and the lowest pain threshold in the four groups. Simultaneously, CCD rats showed higher P2X3 mRNA and protein expression in ipsilateral side of the SDH than the sham operation rats. However, the MWT was increased and expression of P2X3 mRNA and protein in the ipsilateral SDH in CCD rats was decreased 3 days after PGB treatment. Thus, PGB may partially reverse mechanical hyperalgesia in CCD rats by inhibiting P2X3 receptor expression in the ipsilateral SDH. Anat Rec, 296:1907Rec, 296: -1912Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.Abbreviations used: CCD 5 chronic compression of dorsal root ganglion; cDNA 5 complementary deoxyribonucleic acid; DRG 5 dorsal root ganglion; L 5 lumbar segment; mRNA 5 messenger ribonucleic acid; MWT 5 mechanical withdrawal threshold; NS 5 normal saline; PGB 5 pregabalin; RT-PCR 5 reverse transcription-polymerase chain reaction; S 5 sacral segment; SDH 5 spinal dorsal horn.

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Pharmacological characterization and gene expression profiling of an L5/L6 spinal nerve ligation model for neuropathic pain in mice

Cited by 51 publications

References 53 publications

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Intrathecal Administration of AS1928370, a Transient Receptor Potential Vanilloid 1 Antagonist, Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain

Pregabalin Alters Nociceptive Behavior and Expression Level of P2X3 Receptor in the Spinal Dorsal Horn in a Rat Model Induced by Chronic Compression of the Dorsal Root Ganglion

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