Cramer, N. P. | bioRxiv Science

bioRxiv2020

Divergent profiles of fentanyl withdrawal and associated pain in mice and rats

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species strengths as model systems and can inform experimental design in studies of opioid withdrawal.

neuroscience↗

bioRxiv2020

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

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

neuroscience↗