Previously, low frequency stimulation (LFS) of a non-nociceptive touch-sensitive neuron has been found to elicit endocannabinoids-dependent long-term depression (eCB-LTD) in nociceptive synapses in the leech central nervous system (CNS) that requires activation of a presynaptic TRPV-like receptor by postsynaptically-synthesized 2-AG. This capacity of non-nociceptive afferent activity to reduce nociceptive signaling resembles gate control of pain, albeit longer lasting in these synaptic experiments. Having observed eCB-LTD at a single sensory-motor synapse, this study examines the functional relevance of this mechanism. Specifically, whether this form of synaptic plasticity has similar effects at the behavioral level in which additional, intersegmental neural circuits are engaged. Experiments were carried out using a semi-intact preparation that permitted both synaptic recordings and monitoring of the leech whole-body shortening, a defensive withdrawal reflex that was elicited via intracellular stimulation of a single nociceptive neuron (the N-cell). The same LFS of a non-nociceptive afferent that induced eCB-LTD in single synapses also produced an attenuation of the shortening reflex. Similar attenuation of behavior was also observed when 2-AG was applied. LFS-induced behavioral and synaptic depression was blocked by tetrahydrolipstatin (THL), a DAG lipase inhibitor, and by SB366791, a TRPV1 antagonist. The effects of both THL and SB366791 were observed following either bath-application of the drug or intracellular injection into the presynaptic (SB366791) or postsynaptic (THL) neuron. These findings demonstrate a novel, endocannabinoid-based mechanism by which non-nociceptive afferent activity may modulate nocifensive behaviors via action on primary afferent synapses.

PMID:

 

24027102

 

[PubMed – as supplied by publisher]