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The Mechanisms of NMDAR-Dependent Long-Term Potentiation in Nociceptive Synapsese
Sharleen Yuan, MA, PhD, MSIV and Brian D. Burrell, PhD
Chronic pain is a debilitating disorder that affects millions of individuals worldwide. However, treatment and therapy options remain limited, in part, because the basic biological processes regulating nociceptive signaling are not well understood. Therefore, this project examined the modulatory processes underlying nociceptive signaling using the medicinal leech model as a system. Previous studies in the Burrell laboratory have shown that low-frequency stimulation can depress nociceptive signaling through an endocannabinoid-dependent mechanism (Yuan & Burrell, 2010, 2012, 2013a, 2013b).
Endocannabinoids are lipid-based neurotransmitters involved in modulating numerous processes including appetite, emotion, cognition, and nociception (Di Marzo et al., 2004; Elphick, 2012). However, it is not known what patterns of activity result in increases in nociceptive signaling, e.g. long-term potentiation (LTP). Utilizing a tetanic stimulation protocol (high-frequency stimulation (HFS) at 25Hz; 10 spikes with 20 trains at 10sec intervals), we observed LTP in the nociceptive synapses. This potentiation was found to be NMDA receptor-dependent and synapse-specific, similar to other examples of LTP found throughout the central nervous system. Interesting, AP5, an NMDA receptor antagonist, not only blocked the LTP, but unmasked a form of synaptic depression elicited by the HFS. To test whether this synaptic depression was mediated by endocannabinoids, two sets of experiments were carried out.
First, an inhibitor of endocannabinoid synthesis (tetrahydrolipstatin or THL) was injected into the postsynaptic neuron while tetanic stimulation was carried out in the presence of AP5 treatment. THL injection blocked the depression normally observed in AP5+tetanus treatment groups. Second, because a TRPV-like receptor was discovered to be involved in endocannabinoid-mediated depression, experiments were carried out in which the TRPV1 antagonist, SB366791, was injected into the presynaptic neuron during AP5+tetanus treatments. SB366791 injections inhibited the depression observed in AP5+tetanus treatment groups. Taken together, the unmasked depression appeared to be both endocannabinoid- and TRPV-dependent.
These results suggest that strong synaptic stimulation can activate both NMDA receptor-based potentiating and endocannabinoid-dependent depressing processes, but that the potentiating processes dominate and actually suppress the influence of the depressive mechanisms. In addition, while LTP was synapse-specific, endocannabinoid-mediated depression affected both active and inactive nociceptive synapses.