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

Abstract

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.

Keywords: conscious rats; minute ventilation; morphine; peripheral and central opioid receptors; tolerance.

Figure 1

Frequency of breathing (top panel), Tidal Volume (middle panel) and Minute Volume (bottom panel) before (Pre) and following bolus injections of vehicle or naloxone methiodide (NLXmi, 1.5 mg/kg, i.v.) and subsequent injections of morphine (1.0 mg/kg, i.v). The data are presented as mean ± SEM. There were 9 rats in each group.

Figure 2

Inspiratory Time (top panel), Expiratory Time (middle panel) and End Inspiratory Pause (bottom panel) before (Pre) and following bolus injections of vehicle or naloxone methiodide (NLXmi, 1.5 mg/kg, i.v.) and subsequent injections of morphine (1.0 mg/kg, IV). The data are presented as mean ± SEM. There were 9 rats in each group.

Figure 3

Respiratory Drive (Tidal Volume/Inspiratory Time) before (Pre) and following bolus injections of vehicle or naloxone methiodide (NLXmi, 1.5 mg/kg, i.v.) and subsequent injections of morphine (1.0 mg/kg, IV). The data are presented as mean ± SEM. There were 9 rats in each group.

Figure 4

Peak Inspiratory Flow (top panel) and Peak Expiratory Flow (bottom panel) before (Pre) and following bolus injections of vehicle or naloxone methiodide (NLXmi, 1.5 mg/kg, i.v.) and subsequent injections of morphine (1.0 mg/kg, i.v.). The data are presented as mean ± SEM. There were 9 rats in each group.