Abstract
Endocannabinoids are lipid neuromodulators that are synthesized on demand and primarily signal in a retrograde manner to elicit depression of excitatory and inhibitory synapses. Despite the considerable interest in their potential analgesic effects, there is evidence that endocannabinoids can have both pro-nociceptive and anti-nociceptive effects. The mechanisms contributing to the opposing effects of endocannabinoids in nociception need to be better understood before cannabinoid-based therapies can be effectively utilized to treat pain. Using the medicinal leech, Hirudo verbana, this work investigates whether endocannabinoids modulate tonic inhibition onto non-nociceptive afferents. In voltage clamp recordings, we analyzed changes in the tonic inhibition in pressure-sensitive (P) cells following pre-treatment with endocannabinoids, 2-arachidonoylglycerol (2-AG) or anandamide (AEA). We also tested whether high frequency stimulation (HFS) of nociceptive (N) cells could also modulate tonic inhibition. Both endocannabinoid application and N cell HFS depressed tonic inhibition in the P cell. Depression of tonic inhibition by N cell HFS was blocked by SB 366791 (a TRPV1 inhibitor). SB 366791 also prevented 2-AG-and AEA-induced depression of tonic inhibition. HFS-induced depression was not blocked by tetrahydrolipstatin (THL), which prevents 2-AG synthesis, nor AM 251 (a CB1 receptor inverse agonist). These results illustrate a novel activity-dependent modulation of tonic GABA currents that is mediated by endocannabinoid signaling and is likely to play an important role in sensitization of non-nociceptive afferent pathways.
Highlights
Endocannabinoids are lipid neuromodulators synthesized in an activity-dependent manner (Castillo et al, 2012)
Since no spontaneous IPSPs are observed in P cell recordings, we examined whether endocannabinoids mediated tonic GABAergic inhibition instead
Hirudo P cells have been shown to be hyperpolarized by GABA via a negative inward current and this GABA-mediated hyperpolarization/current is blocked by BIC (Sargent et al, 1977; Wang et al, 2015)
Summary
Endocannabinoids are lipid neuromodulators synthesized in an activity-dependent manner (Castillo et al, 2012). Endocannabinoids can modulate excitatory or inhibitory synapses over both short- and long-term time scales, often via presynaptic depression of neurotransmitter release (Castillo et al, 2012). These effects can be homosynaptic or heterosynaptic (Piette et al, 2020). In situations where inhibitory synapses are depressed, this can lead to disinhibition of excitatory synapses (Zhu and Lovinger, 2007; Kim et al, 2019). This disinhibition effect can lead to endocannabinoids eliciting longterm potentiation (LTP) in excitatory, glutamatergic synapses (Carlson et al, 2002; Brown et al, 2013; Cui et al, 2015; Silva-Cruz et al, 2017). While endocannabinoid-mediated depression of glutamatergic synapses in the spinal cord represents a likely anti-nociceptive effect (Kato et al, 2012), endocannabinoid depression of inhibitory synapses has been observed and leads to disinhibition of nociceptive circuitry in the spinal cord that generates a pro-nociceptive effect (Pernia-Andrade et al, 2009)
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