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bioRxiv · 10.1101/2020.10.01.322131

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Cramer, N. P.·Silva-Cardoso, G. K.·Keller, A.
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Abstract

The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices, we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of {micro}-opioid peptide receptors with DAMGO had similar effects, while the k-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 antagonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. Together, these results demonstrate that signaling pathways known to modulate nociception, alter synaptic transmission and neuronal excitability in the lateral parabrachial nucleus and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain. HighlightsO_LIThe parabrachial nucleus (PB) is a hub for processing interoceptive and exteroceptive noxious stimuli, including pain. C_LIO_LISynaptic activity in PB is abnormal in chronic pain. C_LIO_LISynaptic activity in PB is regulated by presynaptic and postsynaptic GABAB, opioid {micro} and k, and cannabinoid CB1 receptors. C_LIO_LIGABAergic presynaptic terminals are most potently regulated by these receptors. C_LIO_LIChanges in the strength of these modulatory pathways may contribute to increased PB excitability and, consequently, chronic pain. C_LI

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Cramer, N. P., Silva-Cardoso, G. K., Keller, A.. 2020-10-01. Control of synaptic transmission and neuronal excitability in the parabrachial nucleus. https://doi.org/10.1101/2020.10.01.322131

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