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

Abstract

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.

The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

“…In addition to its effectiveness in sedation, DEX reportedly has a regulatory effect on VGCC and oxidative stress in neurons202122. Excessive production of mitochondrial ROS and an overload of Ca 2+ through increased TRPM2 and TRPV1 channel activity are two of the main causes of neurodegenerative diseases in hippocampus and induction of peripheral pain in DRG (Fig.…”

“…The results of recent studies show that DEX decreased cerebral ischemia and SCI-induced intracellular ROS production and apoptosis in the brain and DRG of rat, respectively119. Recently, it has been demonstrated that DEX potently inhibits overload Ca 2+ entry through voltage gated calcium channels (VGCC) and glutamate (NMDA) receptors in the DRGs and hippocampus of rats202122. Therefore, DEX may reduce the entry of overload Ca 2+ via modulation of TRPM2 and TRPV1 channel activations in the HIPPO and DRG neurons of rats with cerebral ischemia, and this effect should be clarified.…”

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

“…The exact mechanism that mediates dexmedetomidine analgesia is still unknown. However, previous studies have found that dexmedetomidine inhibits elevations in intracellular Ca 2+ levels in cultured rat dorsal root ganglia cells by its α 2 -adrenoceptor agonist effect [53]. Taken together, these observations suggest that dexmedetomidine may decrease postsynaptic intracellular Ca 2+ concentrations by acting at presynaptic α 2 -adrenoceptors, thereby affecting the expression of P2X7R and ERK phosphorylation.…”

Pharmacological mechanisms involved in the antinociceptive effects of dexmedetomidine in mice

“…In our study, we also demonstrated that systemic ATRO attenuates the antinociceptive effect of DEX. In cultured rat dorsal root ganglia cells, DEX also inhibits muscarinic type 3 receptors and muscarine-induced intracellular Ca 2+ elevation [43]. Moreover, cholinergic pain modulation may also involve first-order neurons (sensory neurons responsible for delivering sensory information to the central nervous system) via muscarinic acetylcholine M2 receptors.…”