Cannabinoids Inhibit Acid-Sensing Ion Channel Currents in Rat Dorsal Root Ganglion Neurons

Abstract

Local acidosis has been found in various pain-generating conditions such as inflammation and tissue injury. Cannabinoids exert a powerful inhibitory control over pain initiation via peripheral cognate receptors. However, the peripheral molecular targets responsible for the antinociceptive effects of cannabinoids are still poorly understood. Here, we have found that WIN55,212-2, a cannabinoid receptor agonist, inhibits the activity of native acid-sensing ion channels (ASICs) in rat dorsal root ganglion (DRG) neurons. WIN55,212-2 dose-dependently inhibited proton-gated currents mediated by ASICs. WIN55,212-2 shifted the proton concentration–response curve downwards, with an decrease of 48.6±3.7% in the maximum current response but with no significant change in the EC50 value. The inhibition of proton-gated current induced by WIN55,212-2 was almost completely blocked by the selective CB1 receptor antagonist AM 281, but not by the CB2 receptor antagonist AM630. Pretreatment of forskolin, an AC activator, and the addition of cAMP also reversed the inhibition of WIN55,212-2. Moreover, WIN55,212-2 altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, WIN55,212-2 attenuated nociceptive responses to injection of acetic acid in rats. These results suggest that WIN55,212-2 inhibits the activity of ASICs via CB1 receptor and cAMP dependent pathway in rat primary sensory neurons. Thus, cannabinoids can exert their analgesic action by interaction with ASICs in the primary afferent neurons, which was novel analgesic mechanism of cannabinoids.

Peripheral gating of pain signals by endogenous lipid mediators

“…Studies in primary cultures of DRG neurons have shown that cannabinoid receptor agonists – dual CB 1 /CB 2 ligands such as CP-55940 and Win-55212-2 or CB 1 -selective ligands such as arachidonyl-2-chloroethylamide (ACEA) – inhibit voltage-gated calcium channels 25 and acid-sensing ion channels (ASICs) 26 , reduce calcium transients evoked by capsaicin activation of TRPV1 24,27 , and block nerve growth factor-induced TRPV1 sensitization 28 . Selective CB 1 receptor antagonists (e.g., rimonabant and AM251) prevent these effects 27,28,29 .…”

Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification

“…It is unclear why the pain behavior of Nse-BMP4;MOR −/− double mutant and Nse-BMP4 mice did not differ. It is possible that another antinociceptive signaling pathway, such as cannabinoid receptor signaling, may be involved in modulating pain behavior in Nse-BMP4 mice [33]. Alternatively the increased expression of SP up-regulation in the mice could be coupled with an unconventional antinociceptive, rather than nociceptive, signaling pathway, analogous to the report by Lin et al [34] that NK1 receptors on muscle afferents can inhibit activity of the acid-sensing ion channel 3.…”

Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

“…Activation of CB 1 receptors, which belong to the G i/o protein-coupled receptor family, induces the inhibition of adenylyl cyclase (AC) leading to the reduction of the cyclic AMP (cAMP) level. WIN55,212-2, an agonist of CB 1 receptors reversibly inhibited ASIC currents in rat primary sensory neurons (91). Furthermore, the mean number of action potentials induced by acid stimulus decreased following activation of CB 1 receptors (91).…”

“…WIN55,212-2, an agonist of CB 1 receptors reversibly inhibited ASIC currents in rat primary sensory neurons (91). Furthermore, the mean number of action potentials induced by acid stimulus decreased following activation of CB 1 receptors (91). Suppression of ASIC currents by CB 1 receptors was abolished by the application of cAMP analogue or the AC activator forskolin (91).…”