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modulation, endocannabinoids, therapy


Endocannabinoids are lipid neuromodulators that are synthesized on demand and primarily signal in retrograde to elicit depression of excitatory and inhibitory synapses. Despite the considerable interest in the analgesic effects of cannabinoids, 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 have been largely unexplored and need to be better understood before cannabinoid-based therapies can be effectively utilized to treat pain. Specifically, we are investigating whether pro-nociceptive endocannabinoid effects could arise, in part, though disinhibition of non-nociceptive afferents following nociceptive sensitizing stimuli using the medicinal leech model system, Hirudo verbana. The conserved arrangement of its nervous system has been well-charted, allowing us to identify precise neurons involved in mechanosensation and to record their electrophysiological properties. This work investigates whether endocannabinoids modulate the potentiation of non-nociceptive synapses through a mechanism that decreases tonic GABAergic input. In voltage clamp recordings, we analyzed changes in the tonic GABA current in a pressure-sensitive (P) cell following pre-treatment with endocannabinoids (2-AG or anandamide) or high frequency stimulation (HFS) of nociceptive (N) cells, which potentiate P cell synapses in an endocannabinoid-dependent manner. Both endocannabinoid application and N cell HFS depressed tonic GABA current in the P cell. Depression of tonic GABA current by N cell HFS potentiation was inhibited following pre-treatment with tetrahydrolipstatin (THL, diacylglycerol lipase inhibitor), AM 251 (CB1 antagonist), or SB 366791 (TRPV antagonist). SB 366791 also prevented 2-AG-induced depression of tonic inhibition. These results illustrate novel activity-dependent modulation of tonic GABA currents that is mediated by endocannabinoid signaling and is likely to play an important role in nociceptive sensitization.

First Advisor

Brian Burrell

Research Area

Basic Biomedical Sciences