Involvement of M3 muscarinic receptors of the spinal cord in formalin-induced nociception in mice

Honda, Kazuo; Harada, Akitsugu; Takáno, Yukio; Kamiya, Hiro-o

doi:10.1016/s0006-8993(99)02456-7

Cited by 54 publications

(25 citation statements)

References 30 publications

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“…Pharmacological studies have yielded contradictory results regarding the molecular identity of the mAChR subtypes mediating the analgesic effects of muscarinic agonists. For example, it has been proposed that muscarinic antinociception is mediated by M 1 (Bartolini et al, 1992;Ghelardini et al, 2000), M 1 and/or M 2 Iwamoto and Marion, 1993), M 1 and/or M 3 (Naguib and Yaksh, 1997), M 2 (Ma et al, 2001), M 3 (Honda et al, 2000), or M 4 (Shannon et al, 1997;Ellis et al, 1999) mAChRs. It is likely that the limited receptor subtype selectivity of the currently available muscarinic agonists and antagonists that were used in these in vivo studies is the primary reason for these discrepant results (Caulfield, 1993;Wess, 1996).…”

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confidence: 99%

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Duttaroy

Gomeza²,

Gan³

et al. 2002

Mol Pharmacol

137

131

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Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M 2 and M 4 receptor subtypes, the two G i /G o -coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M 2 and M 4 mAChRs [M 2 /M 4 double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M 2 /M 4 double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M 2 receptor single-KO mice, but retained full analgesic activity in M 4 receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M 2 and M 4 receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed Ͼ6-fold higher affinity for M 4 than for M 2 receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M 2 and M 4 mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.

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confidence: 99%

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Duttaroy

Gomeza²,

Gan³

et al. 2002

Mol Pharmacol

137

131

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“…According to Metys et al (1969), physostigmine produces an analgesia that is mediated through mAChRs. Honda et al (2000) reported the involvement of M3 mAChRs of the spinal cord in formalin-induced nociception in mice. The muscarinic antagonist atropine and the M3 mAChRs antagonist 4-DAMP were able to inhibit the second phase response of formalin at low doses (0.1-20 ng, i.t.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction

Lima

Costa

Silva

et al. 2016

An. Acad. Bras. Ciênc.

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Geissospermum vellosii (Pao pereira) is a Brazilian tree whose stem barks are rich in indole alkaloids that present intense anticholinesterase activity. The present study evaluated the effects of a stem bark fraction (PPAC fraction) and ethanolic extract (EE) of Pao pereira in classic murine models of infl ammation and pain. The EE and PPAC fraction, both at a dose of 30 mg/kg, signifi cantly reduced mice abdominal constriction induced by acetic acid by 34.8% and 47.5%, respectively. In the formalin test, EE (30 mg/ kg) and PPAC fraction (30 and 60 mg/kg) inhibited only the second phase, by 82.8%, 84.9% and 100%, respectively. Compared with indomethacin, similar doses of EE or PPAC fraction were approximately twice as effective in causing antinociception. PPAC fraction was not effective in the hot plate test but reduced the infl ammatory response at the second (50.6%) and third (57.8%) hours of rat paw edema induced by carrageenan. Antihyperalgesic activity was observed within 30 min with a peak at 2 h (60.1%). These results demonstrate that compounds in PPAC fraction have anti-infl ammatory and antinociceptive activity by a mechanism apparently unrelated to the opioid system. Regardless of similar responses to indomethacin, the effects of PPAC fraction are mainly attributed to acetylcholine actions.

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“…A 27-gauge needle attached to a Hamilton microsyringe was inserted into the subarachnoid space between the L5 and L6 vertebrae of the conscious mouse and 5 ml of the drug solution was slowly injected, as described by Hylden and Wilcox (31). Accurate placement of the needle was confirmed by a quick "flick" of the mouse's tail, as described by Honda et al (32).…”

Section: Drug Preparation and Administrationmentioning

confidence: 99%

Antiallodynic Action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a Betaine/GABA Transporter Inhibitor

et al. 2014

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Abstract. The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC 50 : 5.29, 7.91, and 4.08 mM, respectively. These values were similar to the IC 50 value at BGT-1 (10.6 mM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.

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Involvement of M3 muscarinic receptors of the spinal cord in formalin-induced nociception in mice

Cited by 54 publications

References 30 publications

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction

Antiallodynic Action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a Betaine/GABA Transporter Inhibitor

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