Investigating the role of anaesthetics on the rostral ventromedial medulla: implications for a GABAergic link between ON and OFF cells

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

doi:10.1016/0304-3940(93)90750-f

Cited by 9 publications

(3 citation statements)

References 17 publications

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“…Studies, however, directly assessing MOP‐R evoked changes in GLU or GABA release in the behaving animal are lacking. Such information is important since in vivo recordings require the use of anesthetics, which can affect GABAergic signaling within the RVM (McGaraughty et al. 1993) and slice preparations lack intact neuronal circuits.…”

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confidence: 99%

The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla

Schepers¹,

Mahoney²,

Zapata³

et al. 2007

Journal of Neurochemistry

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Electrophysiological data suggest an involvement of rostral ventromedial medulla (RVM) GABA and glutamate (GLU) neurons in morphine analgesia. Direct evidence that extracellular concentrations of GABA or GLU are altered in response to mu opioid receptor (MOP‐R) activation is, however, lacking. We used in vivo microdialysis to investigate this issue. Basal GABA overflow increased in response to intra‐RVM perfusion of KCl (60 mmol/L). Reverse microdialysis of the MOP‐R agonist d‐Ala(2),NMePhe(4),Gly‐ol(5)]enkephalin (DAMGO) (20–500 μmol/L) produced a concentration‐dependent decrease of RVM GABA overflow. Behavioral testing revealed that concentrations that decreased GABA levels increased thermal withdrawal thresholds. A lower agonist concentration that did not increase GABA failed to alter thermal thresholds. DAMGO did not alter GLU concentrations. However, KCl also failed to modify GLU release. Since rapid, transporter‐mediated uptake may mask the detection of changes in GLU release, the selective excitatory amino acid transporter inhibitor pyrrolidine‐2,4‐dicarboxylic acid (tPDC, 0.6 mmol/L) was added to the perfusion medium for subsequent studies. tPDC increased GLU concentrations, confirming transport inhibition. KCl increased GLU dialysate levels in the presence of tPDC, demonstrating that transport inhibition permits detection of depolarization‐evoked GLU overflow. In the presence of tPDC, DAMGO increased GLU overflow in a concentration‐dependent manner. These data demonstrate that MOP‐R activation decreases GABA and increases GLU release in the RVM. We hypothesize that the opposing effects of MOP‐R on GLU and GABA transmission contribute to opiate antinociception.

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confidence: 99%

The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla

Schepers¹,

Mahoney²,

Zapata³

et al. 2007

Journal of Neurochemistry

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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: 96%

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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“…[1][2][3] However, there is a considerable body of evidence to suggest that enhancement of GABA-mediated synaptic inhibition may be a common mode of action among anaesthetic agents. 1 4 5 In particular, barbiturates, [6][7][8][9][10][11][12] volatile anaesthetics (isoflurane, 1 11 13 14 halothane, 1 13 15 enflurane, 1 13 14 sevoflurane 16 ) and propofol have been reported to enhance the action of GABA within the central nervous system. [17][18][19][20] Indeed, the main sites at which these anaesthetics act to induce anaesthesia are considered to be GABA receptors.…”

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confidence: 99%

Suppression of parasympathetic reflex vasodilatation in the lower lip of the cat by isoflurane, propofol, ketamine and pentobarbital: implications for mechanisms underlying the production of anaesthesia

Ito

Izumi

Sato

et al. 1998

British Journal of Anaesthesia

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We have compared the effects of isoflurane, propofol, ketamine and pentobarbital on parasympathetic reflex vasodilatation to investigate their involvement in GABA-mediated synaptic inhibition, enhancement of which is thought to underlie the action of many anaesthetic agents. In cats anaesthetized with urethane-alpha-chloralose, parasympathetic reflex vasodilation in the ipsilateral lower lip was elicited by electrical stimulation of the central cut end of the lingual nerve. Isoflurane and pentobarbital both produced marked dose-dependent inhibition of this vasodilator response. In contrast, propofol and ketamine had no effect on parasympathetic reflex vasodilation. Administration of a GABA antagonist (picrotoxin) reversed the inhibition produced by isoflurane (previous results) and pentobarbital (present study). Our results suggest that isoflurane and pentobarbitone inhibit parasympathetic reflex vasodilatation via a GABA-mediated mechanism, but that propofol and ketamine have no such effect. Our results with propofol cast doubt on its presumed mechanism of action as an anaesthetic.

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Investigating the role of anaesthetics on the rostral ventromedial medulla: implications for a GABAergic link between ON and OFF cells

Cited by 9 publications

References 17 publications

The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla

The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla

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

Suppression of parasympathetic reflex vasodilatation in the lower lip of the cat by isoflurane, propofol, ketamine and pentobarbital: implications for mechanisms underlying the production of anaesthesia

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