Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

Abstract

This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient.

Keywords: Analgesia, Rats; Arterial blood gases; Fentanyl; Naloxone methiodide; Ventilation.

Fig. 1

Effects of fentanyl (25 µg/kg, i.v.) on Tail-Flick latencies in rats pretreated with (a) vehicle (n=4) or naloxone methiodide (NLXmi; 1.5 mg/kg, i.v., n=4) (upper-left panel) or (b) vehicle (n=5) or naloxone methiodide (NLXmi; 5.0 mg/kg, i.v., n=5) (upper-right panel). The data are also expressed as maximal possible effect (%MPE) (lower panels). All data are presented as mean ± SEM. *P < 0.05, significant change from Post-Drug value. †P < 0.05, NLXmi versus vehicle.

Fig. 2

Effects of fentanyl (25 µg/kg, i.v.) on arterial blood pH, pO₂, pCO₂ and sO₂ values and Alveolar-arterial gradients in conscious rats pretreated with vehicle (saline) or naloxone methiodide (NLXmi; 1.5 mg/kg, i.v.). The terms F1, F5 and F9 refer to values recorded 1, 5 and 9 min after administration of fentanyl. The data are presented as mean ± SEM. There were 6 rats in each group. *P < 0.05, significant change from post-drug value. ^†P < 0.05, NLXmi versus vehicle.

Fig. 3

Effects of fentanyl (25 µg/kg, i.v.) on body temperatures (arithmetic change) in conscious rats pretreated with vehicle (saline), naloxone methiodide (NLXmi; 1.5 or 5.0 mg/kg, i.v.) or naloxone (NLX, 1.5 mg/kg, i.v.). The data are presented as mean ± SEM. There were 6 rats in each group. *P < 0.05, significant change from post-drug value. ^†P < 0.05, NLXmi or NLX versus vehicle.

Fig. 4

Effects of fentanyl (25 µg/kg, i.v.) on frequency of breathing (top panels), tidal volume (middle panels) and minute volume (bottom panels) in rats pretreated with either vehicle or naloxone (NLX; 1.5 mg/kg, i.v.) (left-hand panels) or vehicle or naloxone methiodide (NLXmi; 1.5 mg/kg, i.v.) (right-hand panels). The stippled horizontal line denotes average resting values immediately before injection of fentanyl. The data are presented as mean ± SEM. There were 6 rats in each group.

Fig. 5

Effects of fentanyl (25 µg/kg, i.v.) on inspiratory time (top panels), expiratory time (middle panels) and end inspiratory pause (bottom panels) in rats pretreated with either vehicle or naloxone (NLX; 1.5 mg/kg, i.v.) (left-hand panels) or vehicle or naloxone methiodide (NLXmi; 1.5 mg/kg, i.v.) (right-hand panels). The stippled horizontal line denotes average resting values immediately before injection of fentanyl. The data are presented as mean ± SEM. There were 6 rats in each group.

Fig. 6

Effects of fentanyl (25 µg/kg, i.v.) on peak inspiratory flow (top panels) and peak expiratory flow (bottom panels) in rats pretreated with either vehicle or naloxone (NLX; 1.5 mg/kg, i.v.) (left-hand panels) or vehicle or naloxone methiodide (NLXmi; 1.5 mg/kg, i.v.) (right-hand panels). The stippled horizontal line denotes average resting values immediately before injection of fentanyl. The data are presented as mean ± SEM. There were 6 rats in each group.