Activity-Dependent Modulation of Tonic GABA Currents by Endocannabinoids
Endocannabinoids (eCBs) are lipid neuromodulators that are synthesized on demand and primarily signal in retrograde to elicit depression of excitatory and inhibitory synapses. Chronic pain is often characterized by an initial sensitization, or enhanced response to noxious stimuli. We hypothesize that eCBs contribute to this sensitization mechanism. Despite the considerable public interest in the analgesic effects of eCBs, there is contradictory evidence at the preclinical and clinical research stages that eCBs can also promote pro-nociceptive effects. The mechanisms contributing to the opposing effects of eCBs in nociception have been largely unexplored, and need to be better understood before eCB therapies can be utilized effectively for pain. Specifically, we are investigating whether the pro-nociceptive eCB effects could be arising at the nociceptive or non-nociceptive afferent synapses, and how potentiation and disinhibition coordinate at these synapses during sensitization. We examine eCB-induced synaptic plasticity and its connection to nociception-related learning with the medicinal leech model system, Hirudo verbana. The conserved arrangement of its nervous system has been well-charted by size and position, and allows us to identify precise neurons involved in mechanosensation to record their electrophysiological properties. This work is investigating whether eCBs modulate the potentiation of non-nociceptive synapses through a mechanism that decreases tonic GABAergic input. In voltage clamp recordings, we are analyzing the changes in GABA current in a pressure (P) cell following pre-treatment with eCBs (2-AG or anandamide) in varying combinations with AM 251 (CB1 antagonist), SB 366791 (TRPV antagonist), and tetrahydrolipstatin (THL, DAGL inhibitor). We are also studying whether high frequency stimulation of nociceptive cells, which potentiates P cell synapses in an eCB-dependent manner, depresses tonic GABA current in the P cell, producing a disinhibitory effect. Results from this project will ultimately provide insight into the role of eCB-dependent modulation in tonic GABA currents during sensitization.