The Inhibitory Effects of Alphaxalone on M1 and M3 Muscarinic Receptors Expressed in Xenopus Oocytes

Shiraishi, Munehiro; Minami, Kouichiro; Shibuya, Izumi; Uezono, Yasuhito; Ogata, Junichi; Okamoto, Takashi; Murasaki, Osamu; Kaibara, Muneshige; Ueta, Yoichi; Shigematsu, A.

doi:10.1213/01.ane.0000068985.78588.e1

Cited by 11 publications

(14 citation statements)

References 23 publications

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“…They are synthesised in response to several physiological states, including stress and pregnancy (Hosie et al, 2006). Endogenous neurosteroids are synthesised in the central and peripheral nervous systems from cholesterol, with one of the earliest observations being their anaesthetic properties (Sutton, 1972, Shiraishi et al, 2003, Compagnone and Mellon, 2000, Belelli and Lambert, 2005. It is the function that neurosteroids have on producing anaesthesia that we are most interested.…”

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

“…It has been suggested that alfaxalone may possess antinociceptive effects and potential antinociceptive properties of neurosteroids have been investigated at several receptor sites (Shiraishi et al, 2003, Horishita et al, 2002, Nadeson and Goodchild, 2000, Nadeson and Goodchild, 2001, Winter et al, 2003, Britton et al, 1991. However there is conflicting evidence of antinociceptive activity for alfaxalone.…”

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

“…However there is conflicting evidence of antinociceptive activity for alfaxalone. Spinal muscarinic acetylcholine receptors are involved in antinociception, and inhibition of muscarinic receptor function has been demonstrated for IV anaesthetics and analgesic agents (Shiraishi et al, 2003). Alfaxalone at clinically relevant doses was shown to inhibit M1 and M3 muscarinic receptors expressed in Xenopus laevis oocytes (Shiraishi et al, 2003).…”

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

“…Spinal muscarinic acetylcholine receptors are involved in antinociception, and inhibition of muscarinic receptor function has been demonstrated for IV anaesthetics and analgesic agents (Shiraishi et al, 2003). Alfaxalone at clinically relevant doses was shown to inhibit M1 and M3 muscarinic receptors expressed in Xenopus laevis oocytes (Shiraishi et al, 2003). An alternative antinociceptive pathway has been suggested, in which noradrenergic neurotransmission is enhanced 27 by noradrenaline transporter inhibition (Horishita et al, 2002).…”

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

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The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

Lau¹

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Rodents are routinely anaesthetised for husbandry and biomedical research purposes. All anaesthetics carry a degree of risk, complications and side effects. An ideal anaesthetic for rodents is safe, predictable, alleviates pain and distress and can be performed without specialist training. A survey was created to identify anaesthetic agents frequently administered to rodents currently utilised by the research community. Findings indicated injectable anaesthetics were very commonly used and complications were often associated with use, highlighting the lack of a safe, predictable laboratory rodent anaesthetic protocol.Alfaxalone is a neuroactive steroid injectable anaesthetic agent with a high margin of safety, and is commonly used in veterinary anaesthesia as the Alfaxan® formulation. I sought to establish whether alfaxalone could be used as an injectable anaesthetic agent for laboratory rodents. A plasma pharmacokinetics study was performed using IV and IP Alfaxan® in adult female Wistar rats (7-10 weeks). Mean T 1/2elim for 2 and 5 mg.kg -1 IV was short (~17 minutes), but could not be estimated for IP dosing due to sustained plasma levels for up to 60 minutes after injection. Cl p for IV injection was calculated at 24.5% and 23% of cardiac output respectively. The observed C max was 2.99 mg.L -1 for IP administration, and 2.2 ± 0.9 and 5.2 ± 1.3 mg.L -1 for 2 and 5 mg.kg -1 IV administration respectively. AUC 0-60 was 96 min.mg.L -1 for IP dosing. The relative bioavailability for IP dosing was 26% and 28%, compared to IV doses of 2 and 5mg.kg -1 respectively. Alfaxalone given IP caused longer sleep times than IV dosing, although anaesthesia was not induced in 30% of rats.Importantly, all rats exhibited muscle twitching after alfaxalone administration. I then sought to test whether combining IP injection of Alfaxalone with common premedication agents could improve anaesthetic induction rates and reduce muscle twitching, to provide a viable anaesthetic regimen for rats. Medetomidine (0.5 mg.kg -1 ), medetomidine-butorphanol (0.35 mg.kg -1 -0.2 mg.kg -1 ), Acetylpromazine (ACP) -methadone (3 mg.kg -1 -0.7 mg.kg -1 ) and ACP-xylazine (3 mg.kg -1 -3 mg.kg -1 )were administered IP 10 minutes prior to IP alfaxalone (20 mg.kg -1 ). ACP-xylazine, medetomidine and medetomidine-butorphanol all significantly reduced twitching. Medetomidine-butorphanol provided surgical anaesthesia without prolonged recovery and provided an adequate plane of anaesthesia for short painful surgical procedures.However, none of these premedication agents fully eliminated alfaxalone-induced muscle twitching. I therefore carried out electrophysiological studies of motor neurons (MN), to determine the mechanism causing neuromotor excitation in response to alfaxalone. Previous data has shown that alfaxalone can modulate strychnine-sensitive glycinergic receptors, which may, in part, contribute to the adverse neuromotor excitatory responses manifested as muscle twitching during alfaxalone anaesthesia. The 3 effects of alfaxalone on inhibito...

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Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

Section: Neurosteroids and Their Neuronal Actionsmentioning

confidence: 99%

See 2 more Smart Citations

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

Lau¹

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“…Murasaki et al and Nagase et al [10,11] reported that propofol inhibits M 1 R-mediated signal transduction at the receptor site or the site of interaction between the receptor and associated G proteins. Shiraishi et al [12] recently reported the inhibitory effects of alphaxalone on the M 1 R and M 3 R expressed in Xenopus oocytes. These findings show that intravenous anesthetics inhibit functions of M 1 R and M 3 R.…”

Section: Muscarinic Receptorsmentioning

confidence: 99%

G-protein-coupled receptors as targets for anesthetics

Minami

Uezono

2005

International Congress Series

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Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells

Takizuka

Minami

Uezono

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Dexmedetomidine, an alpha(2)-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the alpha(2)-adrenoceptor. We examined the effects of dexmedetomidine on M(1), M(3), 5-HT(2C), substance P, and orexin 1 receptors in Xenopus oocytes expressing individual receptors. In addition, we investigated the effects of dexmedetomidine on muscarinic receptor-mediated changes in [Ca(2+)](i) in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT(2C)-, or substance P-induced Cl(-) currents and had little inhibition on the orexin A-induced current in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1 microM)-induced Ca(2+)-activated Cl(-) currents in Xenopus oocytes expressing M(1) receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M(3) receptors; 1 nM, 10 nM, 100 nM, and 1 microM dexmedetomidine reduced the current to 66.5 +/- 4.8, 51.3 +/- 12, 34.6 +/- 11, and 26.8 +/- 6.4% of the control value, respectively (EC(50) = 3.5 +/- 0.7 nM). Dexmedetomidine reduced the ACh-induced Cl(-) currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca(2+)](i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M(3) receptors, in addition to its agonistic effects on alpha(2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.

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The Inhibitory Effects of Alphaxalone on M1 and M3 Muscarinic Receptors Expressed in Xenopus Oocytes

Cited by 11 publications

References 23 publications

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

G-protein-coupled receptors as targets for anesthetics

Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells

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