Opioid μ-receptors in medullary raphe region affect the hypoxic ventilation in anesthetized rats

Zhang, Zhenxiong; Xu, Fadi; Zhang, Cancan; Liang, Xiaomin

doi:10.1016/j.resp.2009.07.015

Cited by 23 publications

(23 citation statements)

References 42 publications

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“…With respect to central HX pathways, it is known that microinjection of opioid μ-receptor agonists into the medullary raphe region (Zhang et al, 2009) and commissural NTS (Zhang et al, 2011) suppress HVR. Morphine has numerous potential sites/mechanisms to suppress ventilatory responses to HC.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, microinjections of the μ-OR agonist, DAMGO, into medullary raphe regions of anesthetized rats blunt HVR whereas microinjections of DAMGO into the commissural NTS suppress HVR and HCVR (Zhang et al, 2007, 2009, 2011). The ability of morphine to depress HVR (Berkenbosch et al, 1997; Dahan et al, 1988; Sarton et al, 1999) and HCVR (Sarton et al, 1999) in humans, suggests that opioids and/or metabolites of opioids (Peat et al, 1991) depress carotid body (CB) function and central mechanisms responsive to these challenges (Dahan et al, 1998; Sarton et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Baby¹,

Gruber²,

Young

et al. 2018

European Journal of Pharmacology

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Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Baby¹,

Gruber²,

Young

et al. 2018

European Journal of Pharmacology

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“…Studies in rats have also demonstrated that opioids depress V M and ABG chemistry [3,7-12], blunt the ventilatory responses to hypoxic challenge [13], and depress carotid body chemoafferent responses to hypoxic or hypercapnic challenges [14-18]. It is rightfully assumed that ventilatory control processes per se and the ventilatory responses to hypoxic and/or hypercapnic challenges recover upon the amelioration of the effects of opioids on baseline ventilatory parameters.…”

Section: Introductionmentioning

confidence: 99%

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge

May¹,

Henderson²,

Gruber³

et al. 2013

OJMIP

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This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO2, decreases in pO2 and sO2) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.

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“…Studies in animals have demonstrated that opioids also depress ventilation via central and peripheral effects [see 8–10] including central- [11] and vagal afferent-mediated [12] depression of ventilatory drive; skeletal muscle rigidity in the chest-wall [13]; and increases in pulmonary [14] and upper airway [15] resistances. Moreover, activation of central and peripheral μ-ORs blunt the hypoxic ventilatory response [16], and opioids such morphine depress the responsiveness of carotid body chemoafferents to hypoxia and hypercapnia [17–19]. …”

Section: Introductionmentioning

confidence: 99%

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral <i>µ</i>-opioid receptors

Henderson¹,

May²,

Gruber³

et al. 2013

OJMIP

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The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not.

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Opioid μ-receptors in medullary raphe region affect the hypoxic ventilation in anesthetized rats

Cited by 23 publications

References 42 publications

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral <i>µ</i>-opioid receptors

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Opioid μ-receptors in medullary raphe region affect the hypoxic ventilation in anesthetized rats

Cited by 23 publications

References 42 publications

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral &lt;i&gt;&#181;&lt;/i&gt;-opioid receptors

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Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral <i>µ</i>-opioid receptors