Inhibition of fatty acid amide hydrolase unmasks CB₁ receptor and TRPV1 channel‐mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey

Abstract

BACKGROUND AND PURPOSEWhile arachidonyl ethanolamine (anandamide) produces pharmacological effects mediated by cannabinoid CB1 receptors, it is also an agonist at the transient receptor potential vanilloid type 1 (TRPV1) ion channel. This study examined the cellular actions of anandamide in the midbrain periaqueductal grey (PAG), a region implicated in the analgesic actions of cannabinoids, and which expresses both CB1 receptors and TRPV1. EXPERIMENTAL APPROACHIn vitro whole cell patch clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) were made from rat and mouse PAG slices. KEY RESULTSCapsaicin (1 mM) increased the rate, but not the amplitude of miniature EPSCs in subpopulations of neurons throughout the rat and mouse PAG. Capsaicin had no effect on miniature EPSCs in PAG neurons from TRPV1 knock-out mice. In mouse PAG neurons, anandamide (30 mM) had no effect on the rate of miniature EPSCs alone, or in the presence of either the CB1 antagonist AM251 (3 mM) or the TRPV1 antagonist iodoresiniferatoxin (300 nM). Anandamide produced a decrease in miniature EPSC rate in the presence of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 mM). By contrast, anandamide produced an increase in miniature EPSC rate in the presence of both URB597 and AM251, which was absent in TRPV1 knock-out mice. CONCLUSIONS AND IMPLICATIONSThese results suggest that the actions of anandamide within PAG are limited by enzymatic degradation by FAAH. FAAH blockade unmasks both presynaptic inhibition and excitation of glutamatergic synaptic transmission which are mediated via CB1 receptors and TRPV1 respectively.

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…AM6701 afforded greater protection against the excitotoxic events than AM6702, an inhibitor more potent toward FAAH than MAGL. Blocking endocannabinoid deactivation mechanisms represents an exploitable avenue for reducing excitotoxic damage through dual targeting of pharmacotherapeutic pathways [13,[45][46][47][48]. Blocking the inactivation of endocannabinoid responses is 1 such strategy to promote protective signaling after pathological injury and ameliorate cellular disturbances associated with excitotoxicity.…”

“…A bifunctional effect is perhaps occurring in which basal AMPA signals are enhanced through kinase activity, whereas excitotoxic activation of glutamate receptors is reduced through the positive modulation of cannabinergic signaling. An alternative bifunctional mechanism for the modulation of glutamatergic transmission has been proposed, mediated by the inhibition of FAAH [46]. The protective nature of AM6701 that influences the synapse is key, in which preservation of presynaptic and postsynaptic integrity likely explains the corresponding protection at the Fig.…”

Why do cannabinoid receptors have more than one endogenous ligand?

“…This results in glutamate release in the rostral ventromedial medulla (RVM) and activation of OFF neurons in this area, with subsequent anti-nociception. Furthermore, pre-synaptic TRPV1 activation by endovanilloids stimulates glutamate release also in the PAG [104], which results in the facilitation of metabotropic glutamate receptor-induced impairment of GABA release via endocannabinoids acting in a retrograde and CB1-mediated manner, and again stimulates the descending anti-nociceptive pathway [105].…”

Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

“…promote prolonged neurotransmitter release from the terminals (Medvedeva et al, 2008). and in several brain regions (Gibson et al, 2008;Maione et al, 2009;Kawahara et al, 2011see Edwards, 2014& Ryskamp et al, 2014 such as the hippocampus (Gibson et al, 2008). This process shapes pain receptor sensitization in the peripheral nervous system (Medvedeva et al, 2008) and long-term potentiation for memory formation in the hippocampus (Gibson et al, 2008).…”

“…In the CNS, TRPV1 is likely gated by endovanilloids such as anandamide (Gibson et al, 2008;Maione et al, 2011;Kawahara et al, 2011;Ryskamp et al, 2014). In both LTP and LTD, TRPV1 activation by anandamide results in Ca 2+ influx, prolonged increases in intracellular [Ca 2+ ], and subsequent sustained neurotransmitter release from presynaptic terminals.…”