Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Abstract

In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pronociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain-free periods.

CO2-inhibited neurons in the medullary raphé are GABAergic

“…Hellman and Mason (2012) propose that raphé magnus collectively integrates inputs and regulates sympathetic/parasympathetic tone, to produce appropriate homeostatic balance. This “gain-setting” is accomplished, in part, through activity of pain-sensing “OFF” cells (93% of which are GABAergic; Winkler et al, 2006).…”

“…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.…”

Acute and Chronic Pain in Children

“…Descending inputs from the brainstem control nociceptive transmission at the DH (Ren and Dubner 2002;Pitkanen et al 1998;Gebhart 2004;Tillu et al 2007;Bee and Dickenson 2008;Zhang et al 2009;Basbaum and Fields 1984;Fields and Basbaum 1978;Fields and Heinricher 1989;Hellman and Mason 2012;Hathway et al 2009aHathway et al , 2012. Rodent brainstem nuclei differentiate between E11 and E16, and become identifiable by E18 (Altman and Bayer 1984).…”

Medullary circuits for nociceptive modulation

“…We recorded from both on and off cells in unanesthetized mice who cycled through wake and sleep states [20••]. Morphine suppressed the noxious stimulus-evoked responses of both cell classes while producing no change in background discharge rates.…”

“…Striking evidence that tonic off cell activity is also insufficient for antinociception comes from the finding that background off cell discharge is greater before noxious stimulus trials that result in withdrawals than before those that do not produce withdrawals in the unanesthetized mouse [20••]. The observation of greater off cell activity before responding trials than before non-responding trials is frankly inconsistent with the tonic model described above which predicts that greater off cell activity should lead to decreased nociceptive responses (Fig.…”