Differential respiratory patterns induced by opioids applied to the ventral medullary and dorsal pontine surfaces of cats

Hurlé, María A.; Mediavilla, A.; Flórez, Jesús

doi:10.1016/0028-3908(85)90100-5

Cited by 52 publications

(41 citation statements)

References 25 publications

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“…Direct administration of morphine into the KFN and medial parabrachial nucleus regions slows respiratory rhythm by prolonging the inspiratory and expiratory phases (23,24,55). There are functional synaptic connections between KFN neurons and ventral respiratory group inspiratory and expiratory neurons (49), and computer modeling of the pontomedullary respiratory network suggests that the timing and patterns of discharge of all the neurons tested for opiate responsiveness in this study can be influenced by excitatory synaptic inputs from pontine neurons (46).…”

Section: Discussionmentioning

confidence: 97%

“…From the in vitro studies, it seems clear that the PBC is a major site where opiate substances slow rhythm (34, 37). However, opiates are known to have actions at other sites in the adult intact respiratory network that contribute to slowing of breathing (20,23,24,55).…”

Section: Discussionmentioning

confidence: 99%

“…Opiate slowing of respiratory rhythm, leading to arrest of breathing after the highest doses, has been the topic of many experimental investigations (2,10,14,16,22,24,30,34,37,48,52,60). According to most recent studies, rhythm slowing seems to be principally related to depression of inspiratory interneurons in the pre-Bötzinger complex (PBC) (15, 34, 37), a region within the ventrolateral respiratory column (VRC) that seems to be critical for generation of respiratory rhythm (40, 52).…”

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confidence: 99%

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Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

Lalley¹

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Lalley, Peter M. Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons. Am J Physiol Regul Integr Comp Physiol 290: R1387-R1396, 2006. First published November 10, 2005 doi:10.1152/ajpregu.00530.2005.-Opiates have effects on respiratory neurons that depress tidal volume and air exchange, reduce chest wall compliance, and slow rhythm. The most dose-sensitive opioid effect is slowing of the respiratory rhythm through mechanisms that have not been thoroughly investigated. An in vivo dose-response analysis was performed on medullary respiratory neurons of adult cats to investigate two untested hypotheses related to mechanisms of opioid-mediated rhythm slowing: 1) Opiates suppress intrinsic conductances that limit discharge duration in medullary inspiratory and expiratory neurons, and 2) opiates delay the onset and lengthen the duration of discharges postsynaptically in phase-regulating postinspiratory and late-inspiratory neurons. In anesthetized and unanesthetized decerebrate cats, a threshold dose (3 g/kg) of the -opioid receptor agonist fentanyl slowed respiratory rhythm by prolonging discharges of inspiratory and expiratory bulbospinal neurons. Additional doses (2-4 g/kg) of fentanyl also lengthened the interburst silent periods in each type of neuron and delayed the rate of membrane depolarization to firing threshold without altering synaptic drive potential amplitude, input resistance, peak action potential frequency, action potential shape, or afterhyperpolarization. Fentanyl also prolonged discharges of postinspiratory and late-inspiratory neurons in doses that slowed the rhythm of inspiratory and expiratory neurons without altering peak membrane depolarization and hyperpolarization, input resistance, or action potential properties. The temporal changes evoked in the tested neurons can explain the slowing of network respiratory rhythm, but the lack of significant, direct opioid-mediated membrane effects suggests that actions emanating from other types of upstream bulbar respiratory neurons account for rhythm slowing.fentanyl; medullary respiratory neurons; phrenic nerve activity; naloxonazine; naltrindole OPIATES ARE WELL KNOWN for their ability to depress ventilation by slowing breathing frequency and reducing tidal volume, gas exchange, upper airway patency, and chest wall compliance (3,4,36,39). They also blunt respiratory network responsiveness to hypoxia and CO 2 /acidosis (11,25,51,60).Opiate slowing of respiratory rhythm, leading to arrest of breathing after the highest doses, has been the topic of many experimental investigations (2,10,14,16,22,24,30,34,37,48,52,60). According to most recent studies, rhythm slowing seems to be principally related to depression of inspiratory interneurons in the pre-Bötzinger complex (PBC) (15, 34, 37), a region within the ventrolateral respiratory column (VRC) that seems to be critical for generation of respiratory rhythm (40, 52). However, endogenous opioid peptides are distributed throughout the bulbar respiratory ...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

Lalley¹

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…These clinically available -opioid receptor drugs, of which morphine and fentanyl remain the most widely used, also produce respiratory depression at therapeutic doses. The rostrodorsal surface of the pons, the nucleus tractus solitarius, and the nucleus ambiguous are specific sites linked to respiratory depression stemming from the use of opioids (Morin-Surun et al, 1984;Hurle et al, 1985). Studies have compared the ratio of analgesia to respiratory depression in a series of morphine-like opioids.…”

mentioning

confidence: 99%

DPI-3290 [(+)-3-((α-R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A Mixed Opioid Agonist with Potent Antinociceptive Activity

Gengo¹,

Pettit²,

O'Neill³

et al. 2003

J Pharmacol Exp Ther

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Compound (ϩ)-3-((␣-R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide , is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25°C using membranes from rat brain or guinea pig cerebellum, the K i values measured for DPI-3290 at ␦-, -, and -opioid receptors were 0.18 Ϯ 0.02, 0.46 Ϯ 0.05, and 0.62 Ϯ 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC 50 values of 1.0 Ϯ 0.3, 6.2 Ϯ 2.0, and 25.0 Ϯ 3.3 nM at ␦-, -, and -receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at ␦-, -, and -receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC 50 value of 3.4 Ϯ 1.6 nM at -opioid receptors and 6.7 Ϯ 1.6 nM at -opioid receptors. Intravenous administration of 0.05 Ϯ 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.Nucleotide sequences for three distinct pertussis toxinsensitive heterotrimeric GTP binding protein-coupled opioid receptors have been reported with approximately 65% homology existing between their amino acids (Kieffer et al., 1992; Chen et al., 1993a,b). These distinct opioid receptors termed , ␦, and are the binding sites for the endogenous peptide molecules endorphins, enkephalins, and dynorphins that have been shown to elicit a variety of pharmacological actions (Chang, 1984). The most notable of these opioid receptormediated actions is analgesia.Opioids produce their therapeutic effects by acting at the same receptors as the endogenous opioid peptides (Erspamer et al., 1989). They alter synaptic transmission by modulating the presynaptic release of neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and substance P (Hagelberg et al., 2002). Changes in receptor-operated potassium currents, adenylate cyclase activity and intracellular free ionized calcium concentrations all have been reported to contribute to these changes in synaptic transmission (Fan and Crain, 1995;Murthy and Makhlouf, 1996). To date, hyperpolarization of membrane potential and the corresponding effects on voltage-sensitive calcium channels (Tang et al., 1994) togeth...

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“…In vivo studies in the adult anesthetized or decerebrate cat suggested that the rostral pons was likely involved in rhythm changes in adult mammals (286,287). Direct administration of morphine into the Kölliker-Fuse nucleus (KFN) and medial parabrachial nucleus regions slowed respiratory rhythm by prolonging the inspiratory and expiratory phases (286,287).…”

Section: Opioid Effects: Insights From In Vivo Animal Datamentioning

confidence: 98%

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

Stuth

Stucke

Zuperku

2012

Comprehensive Physiology

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This article provides a comprehensive, up to date summary of the effects of volatile, gaseous, and intravenous anesthetics and opioid agonists on ventilatory control. Emphasis is placed on data from human studies. Further mechanistic insights are provided by in vivo and in vitro data from other mammalian species. The focus is on the effects of clinically relevant agonist concentrations and studies using pharmacological, that is, supraclinical agonist concentrations are de-emphasized or excluded.

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Differential respiratory patterns induced by opioids applied to the ventral medullary and dorsal pontine surfaces of cats

Cited by 52 publications

References 25 publications

Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

DPI-3290 [(+)-3-((α-R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A Mixed Opioid Agonist with Potent Antinociceptive Activity

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

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