Abstract
Opioids are widely used medicinally as analgesics and abused for hedonic effects, actions that are each complicated by substantial risks such as cardiorespiratory depression. These drugs mimic peptides such as β-endorphin, which has a key role in endogenous analgesia. The β-endorphin in the central nervous system originates from pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and nucleus of the solitary tract (NTS). Relatively little is known about the NTSPOMC neurons but their position within the sensory nucleus of the vagus led us to test the hypothesis that they play a role in modulation of cardiorespiratory and nociceptive control. The NTSPOMC neurons were targeted using viral vectors in a POMC-Cre mouse line to express either opto-genetic (channelrhodopsin-2) or chemo-genetic (Pharmacologically Selective Actuator Modules). Opto-genetic activation of the NTSPOMC neurons in the working heart brainstem preparation (n = 21) evoked a reliable, titratable and time-locked respiratory inhibition (120% increase in inter-breath interval) with a bradycardia (125±26 beats per minute) and augmented respiratory sinus arrhythmia (58% increase). Chemo-genetic activation of NTSPOMC neurons in vivo was anti-nociceptive in the tail flick assay (latency increased by 126±65%, p<0.001; n = 8). All effects of NTSPOMC activation were blocked by systemic naloxone (opioid antagonist) but not by SHU9119 (melanocortin receptor antagonist). The NTSPOMC neurons were found to project to key brainstem structures involved in cardiorespiratory control (nucleus ambiguus and ventral respiratory group) and endogenous analgesia (periaqueductal gray and midline raphe). Thus the NTSPOMC neurons may be capable of tuning behaviour by an opioidergic modulation of nociceptive, respiratory and cardiac control.
Highlights
Opioids have been used for several thousand years for their potent mood altering and analgesic properties [2]
This has led to the proposition that opioidergic systems may target the nucleus of the solitary tract (NTS) to regulate both nociceptive and autonomic function [10, 24, 25], the chemo-architectural complexity and cellular heterogeneity of the NTS has impeded further exploration of this hypothesis. To test this hypothesis, we used selective opto- and chemo-genetic [1, 26] techniques in POMC-Cre mice [27] to test the hypothesis that the NTSPOMC neurons modulate cardiorespiratory and nociceptive processing, by an opioidergic action. We show that this small cluster of several hundred NTSPOMC neurons extend extensive projections to key autonomic and pain control regions within the brainstem to exert a potent influence on cardiorespiratory control and on nociceptive processing, which is mediated by opioid release
Using a combination of viral vector-mediated transduction of genetic actuators with Crerecombinase targeting [27] we show that activation of the small cluster of POMC neurons in the NTS exerts strong effects on cardiorespiratory control and on nociceptive processing
Summary
Opioids have been used for several thousand years for their potent mood altering and analgesic properties [2]. The selective genetic ablation of β-endorphin produces a specific deficit in stress-induced analgesia [11] Given their analgesic actions, considerable effort has been invested to delineate the characteristics of the opioid peptides and receptor systems with the aim of identifying new targets that may be free of limiting side effects such as cardiorespiratory depression [3]. There is evidence that activation of opioid receptors in the NTS can exert potent effects on cardiorespiratory control This has led to the proposition that opioidergic systems may target the NTS to regulate both nociceptive and autonomic function [10, 24, 25], the chemo-architectural complexity and cellular heterogeneity of the NTS has impeded further exploration of this hypothesis. We show that this small cluster of several hundred NTSPOMC neurons extend extensive projections to key autonomic and pain control regions within the brainstem to exert a potent influence on cardiorespiratory control and on nociceptive processing, which is mediated by opioid release
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call