title: Long-term depression of nociceptive synapses by non-nociceptive afferent activity: role of endocannabinoids, Ca²+, and calcineurin.
abstract: Activity in non-nociceptive afferents is known to produce long-lasting decreases in nociceptive signaling, often referred to as gate control, but the cellular mechanisms mediating this form of neuroplasticity are poorly understood. In the leech, activation of non-nociceptive touch (T) mechanosensory neurons induces a heterosynaptic depression of nociceptive (N) synapses that is endocannabinoid-dependent. This heterosynaptic, endocannabinoid-dependent long-term depression (ecLTD) is observed where the T- and N-cells converge on a common postsynaptic target, in this case the motor neuron that innervates the longitudinal muscles (L-cells) that contributes to a defensive withdrawal reflex. Depression in the nociceptive synapse required both presynaptic and postsynaptic increases in intracellular Ca²⁺. Activation of the Ca²⁺-sensitive protein phosphatase calcineurin was also required, but only in the presynaptic neuron. Heterosynaptic ecLTD was unaffected by antagonists for NMDA or metabotropic glutamate receptors, but was blocked by the 5-HT₂ receptor antagonist ritanserin. Depression was also blocked by the CB1 receptor antagonist rimonabant, but this is thought to represent an effect on a TRPV-like receptor. This heterosynaptic, endocannabinoid-dependent modulation of nociceptive synapses represents a novel mechanism for regulating how injury-inducing or painful stimuli are transmitted to the rest of the central nervous system.
authors.affiliation: Sanford School of Medicine at The University of South Dakota, Division of Basic Biomedical Sciences, Neuroscience Group, 414 E. Clark Street, Lee Med Bldg, Vermillion, SD, USA.
authors.forename: Sharleen
authors.initials: S
authors.lastname: Yuan
authors.forename: Brian D
authors.initials: BD
authors.lastname: Burrell
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D063388:Endocannabinoids / Q000502:physiology*; D007865:Leeches; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology*; D013569:Synapses / Q000502:physiology
chemical_list: D063388:Endocannabinoids; D019703:Calcineurin; D002118:Calcium