Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats

Abstract

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

CO2-inhibited neurons in the medullary raphé are GABAergic

“…This “gain-setting” is accomplished, in part, through activity of pain-sensing “OFF” cells (93% of which are GABAergic; Winkler et al, 2006). These raphé magnus OFF cells also decrease discharge during spontaneous tachypnea, and when stimulated, produce respiratory depression and exaggerated respiratory sinus arrhythmia indicative of parasympathetic activation (Hellman and Mason, 2012; Hellman et al, 2007; 2009;). Verner and colleagues (2004; 2008) proposed that the dramatic apnea, bradycardia, and hypotension resulting from stimulation of raphé magnus was caused by activation of inhibitory (likely GABA) neurons that project to brain respiratory and cardiovascular sites.…”

Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects

“…Opioids are reported to depress breathing following injections into the pre-Botzinger nucleus, other dorsal and ventral respiratory group nuclei, rostral ventromedial medulla, and caudal medial medulla (Zhang et al, 2007; Phillips et al, 2012; Hellman et al, 2009; Lalley, 2006; Manzke et al, 2003; Pattinson, 2008). There are numerous discrepancies in the literature, many of which are due to species, anesthesia, or other experimental variables.…”

μ-Opioid modulation in the rostral solitary nucleus and reticular formation alters taste reactivity: evidence for a suppressive effect on consummatory behavior

“…In vitro studies have demonstrated that microinjecting Damgo into the pre-Botzinger complex significantly slows respiratory frequency assessed by recording from hypoglossal rootlets (13,18,29). Additionally, in vivo experiments in several mammalian species have revealed that intravenous infusions of opioids can suppress the respiratory rate in intact or decerebrate animals (22,45,49), although rate increases or decreases can occur with localized infusions into different brain stem sites (25,41,49). Together with the current study, these results suggest that opioids act in the brain stem to modulate the frequency of multiple types of rhythmic behaviors.…”