Two distinct unit activity responses to morphine in the rostral ventromedial medulla of awake rats

McGaraughty, Steve; Reinis, Stanislav; Tsoukatos, J.

doi:10.1016/0006-8993(93)90385-z

Cited by 23 publications

(10 citation statements)

References 17 publications

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“…As Martin et al (1992) did not isolate or record from any OFF cells, their conclusions concerned ON cells exclusively. A different group administered a high dose of morphine to unanesthetized rats and recorded the background discharge of RM units that were not characterized by their response to somatic stimulation (McGaraughty et al, 1993). The background discharge of 12 of 20 neurons increased and that of 8 neurons decreased in response to systemic morphine.…”

Section: The Tonic Discharge Of On and Off Cells Is Not Altered By Momentioning

confidence: 99%

“…Two major differences may account for the different results obtained. First, the cell types recorded by McGaraughty et al (1993) are unclear. Second, McGaraughty et al (1993 used a high dose of morphine, which elicits behavioral changes in awake animals (da Silva and Rocha e Silva, 1971;Chaillet et al, 1983;Winters et al, 1988).…”

Section: The Tonic Discharge Of On and Off Cells Is Not Altered By Momentioning

confidence: 99%

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Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Hellman

Mason

2012

J. Neurosci.

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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.

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Section: The Tonic Discharge Of On and Off Cells Is Not Altered By Momentioning

confidence: 99%

Section: The Tonic Discharge Of On and Off Cells Is Not Altered By Momentioning

confidence: 99%

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Hellman

Mason

2012

J. Neurosci.

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“…Recently, McGaraughty et al (1993) reported that all units (n = 20) studied in the awake rat were either activated or inhibited by systemic morphine. This result indicates that characteristic on-and off-cell, but not neutral-cell-type, responses are present in the awake preparation.…”

Section: -Ht and Opioid Analgesiamentioning

confidence: 99%

“…Off cells increase their firing rate just prior to nociceptive withdrawal reflexes and become continuously active following systemic or supraspinal opioid administration. Although some investigators have not observed off cells in awake rats (Oliveras et al, 1990;Martin et al, 1992) recently McGaraughty et al (1993) have demonstrated characteristic off-cell responses to systemic morphine in awake rats. On cells exhibit responses opposite to those of off cells; they increase their firing rate in response to noxious stimuli and are inhibited by morphine administration.…”

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confidence: 99%

Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla

1994

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Neurons in the rostral ventromedial medulla (RVM) are the major source of serotonergic projections to the dorsal horn. A large body of evidence implicates RVM serotonergic neurons in the modulation of spinal nociceptive transmission. Three physiological classes of RVM neurons, on, off, and neutral cells, are postulated to have different nociceptive modulatory effects on spinal nocifensor reflexes. This study was undertaken to determine which RVM cell class(es) contains 5- HT. In anesthetized rats, RVM neurons were identified by their responses to noxious cutaneous stimuli, intracellularly labeled, and processed for 5-HT immunocytochemistry. Labeled neurons were examined with epifluorescence and imaged using a confocal laser microscope. A total of 25 RVM neurons were intracellularly labeled. No off (n = 9) or on (n = 8) cells were serotonergic. Half of the neutral cells (4 of 8) demonstrated 5-HT immunoreactivity. These results call for a reevaluation of the mechanisms of RVM modulatory influence on spinal cord nociceptive transmission. The finding that some neutral cells are serotonergic strongly suggests that serotonergic neutral cells are involved in the modulation of spinal nociceptive transmission. Additionally, inhibition of spinal nociceptive transmission by off cells is unlikely to involve 5-HT release. Finally, since opioid administration does not alter the firing of RVM neutral cells, the results of the present study indicate that serotonergic RVM neurons do not directly mediate the effects of supraspinal opioids in the rat.

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“…That is, by definition, every RVM neuron recorded can be identified as an ON-, OFF-, or NEUTRAL-cell. These three cell classes have been identified in barbiturate-, ketamine-, and isoflurane-anesthetized rats as well as in decerebrate-unanesthetized and awake animals (Clarke et al 1994;Heinricher et al 2010b;Mason 1995, 1999;McGaraughty et al 1993aMcGaraughty et al , 1993b. ON-cells facilitate nociception, and local or systemically administered -opioids suppress ON-cell activity.…”

Section: Discussionmentioning

confidence: 95%

Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression

Phillips

Cleary

Nalwalk

et al. 2012

Journal of Neurophysiology

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Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the μ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells, OFF-cells, and NEUTRAL-cells. Since opioids are known to activate OFF-cells but suppress ON-cell firing, the differential respiratory response to these two analgesic drugs is best explained by their opposing effects on the activity of RVM ON-cells. These findings show that pain relief can be separated pharmacologically from respiratory depression and identify RVM OFF-cells as important central targets for continued development of potent analgesics with fewer side effects.

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Two distinct unit activity responses to morphine in the rostral ventromedial medulla of awake rats

Cited by 23 publications

References 17 publications

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla

Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression

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