Endocannabinoid-mediated potentiation of nonnociceptive synapses contributes to behavioral sensitization

Abstract

Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect will result in disinhibition and would therefore be expected to produce an increase in neural circuit output. However, there have been no examples directly linking endocannabinoid-mediated disinhibition to a change in a functional neurobehavioral circuit. The present study uses the well-characterized central nervous system of the medicinal leech, Hirudo verbana, to examine the functional/behavioral relevance of endocannabinoid modulation of an identified afferent synapse. Bath application of 2-AG potentiates synaptic transmission by pressure-sensitive sensory neurons (P cells) as well as the magnitude of the defensive shortening reflex elicited by P-cell stimulation. This potentiation requires activation of TRPV-like channels. Endocannabinoid/TRPV signaling was found to produce sensitization of the shortening reflex elicited by either direct stimulation of nearby nociceptive afferents (N cells) or noxious stimulation applied to skin several segments away. In both cases, heterosynaptic potentiation of P-cell synapses was observed in parallel with an increase in the magnitude of elicited shortening and both synaptic and behavioral effects were blocked by pharmacological inhibition of 2-AG synthesis or TRPV-like channel activation. Serotonin (5-HT) is known to play a critical role in sensitization in Hirudo and other animals, and the 5-HT receptor antagonist ritanserin also blocked behavioral sensitization and the accompanying synaptic potentiation. These findings suggest a novel, endocannabinoid-mediated contribution to behavioral sensitization that may interact with known 5-HT-dependent modulatory processes. NEW & NOTEWORTHY There is considerable interest in the analgesic potential of cannabinoids. However, there is evidence that the cannabinoid system can have both pro- and antinociceptive effects. This study examines how an endogenous cannabinoid transmitter can potentiate nonnociceptive synapses and enhance their capacity to elicit a nocifensive behavioral response.

Interaction between NMDA Receptor- and Endocannabinoid-Mediated Modulation of Nociceptive Synapses

“…In this situation, potentiation of the P cell synapses was due to endocannabinoid-mediated depression of GABAergic input to P cells, resulting in a persistent form of disinhibition. These findings were replicated in semi-intact preparations in which HFS of N cells in the same segment or noxious stimuli delivered several segments away produced endocannabinoid-mediated potentiation of P cell synapses and sensitization of reflexive withdrawal behaviors elicited by P cell activation 53 .…”

Are the persistent effects of “gate control” stimulation on nociception a form of generalization of habituation that is endocannabinoid-dependent?

“…Interestingly, it appears that different patterns of afferent stimulation selectively activate either the endocannabinoid-mediated depression of nociceptive pathways or an endocannabinoid-mediated. potentiation of P cell synaptic pathways (Wang & Burrell, 2016, 2018; Yuan & Burrell, 2013b).…”

The Endocannabinoid System and Invertebrate Neurodevelopment and Regeneration

“…While CB1 receptors are considered the primary neuronal cannabinoid receptor responsible for endocannabinoid-mediated processes within the CNS, recent evidence has demonstrated the expression of central CB2 receptors, both on glial and neuronal cell populations [ 59 ]. Although the precise role of central CB2 receptors remains unclear, their intracellular expression in medial prefrontal cortical pyramidal neurons is thought to contribute to the opening of calcium-activated chloride channels, and subsequent reductions in neuronal firing, further highlighting the complex and nuanced influence of endocannabinoid signaling on synaptic communication [ 48 , 75 ].…”