Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl

Abstract

Fentanyl is a high-potency opioid receptor agonist that elicits profound analgesia and suppression of breathing in humans and animals. To date, there is limited evidence as to whether changes in oxidant stress are important factors in any of the actions of acutely administered fentanyl. This study determined whether the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), or a potent antioxidant, N-acetyl-L-cysteine methyl ester (L-NACme), modify the cardiorespiratory and analgesic actions of fentanyl. We examined whether the prior systemic injection of Tempol or L-NACme affects the cardiorespiratory and/or analgesic responses elicited by the subsequent injection of fentanyl in isoflurane-anesthetized and/or freely moving male Sprague-Dawley rats. Bolus injections of Tempol (25, 50 or 100 mg/kg, IV) elicited minor increases in frequency of breathing, tidal volume and minute ventilation. The ventilatory-depressant effects of fentanyl (5 μg/kg, IV) given 15 min later were dose-dependently inhibited by prior injections of Tempol. Tempol elicited dose-dependent and transient hypotension that had (except for the highest dose) resolved when fentanyl was injected. The hypotensive responses elicited by fentanyl were markedly blunted after Tempol pretreatment. The analgesic actions of fentanyl (25 μg/kg, IV) were not affected by Tempol (100 mg/kg, IV). L-NACme did not modify any of the effects of fentanyl. We conclude that prior administration of Tempol attenuates the cardiorespiratory actions of fentanyl without affecting the analgesic effects of this potent opioid. As such, Tempol may not directly affect opioid-receptors that elicit the effects of fentanyl. Whether, the effects of Tempol are solely due to alterations in oxidative stress is in doubt since the powerful antioxidant, L-NACme, did not affect fentanyl-induced suppression of breathing.

Keywords: cardiorespiratory depression; fentanyl; sprague-dawley rats; superoxide dismutase; tempol.

FIGURE 1

The changes in ventilatory parameters elicited by bolus injections of vehicle (VEH) or Tempol (25, 50 or 100 mg/kg, IV) and subsequent injections of fentanyl (5 μg/kg, IV) in isoflurane-anesthetized rats. There were 12 rats in the vehicle group, and 3, 5 and 12 rats in the 25, 50 and 100 mg/kg Tempol groups, respectively. The data presented are mean ± SEM.

FIGURE 2

The changes in mean (MAP), diastolic (DBP) and systolic (SBP) arterial blood pressures and heart rate elicited by bolus injections of vehicle (VEH) or Tempol (25, 50 or 100 mg/kg, IV) and subsequent injections of fentanyl (5 μg/kg, IV) in isoflurane-anesthetized rats. There were 12 rats in the vehicle group, and 3, 5 and 12 rats in the 25, 50 and 100 mg/kg Tempol groups, respectively. The data presented are mean ± SEM.

FIGURE 3

The peak changes in ventilatory parameters (top panel) and cardiovascular parameters (bottom panel) elicited by bolus injections of vehicle (VEH) or Tempol (25, 50 or 100 mg/kg, IV, designated T25, T50 and T100) and subsequent injections of fentanyl (5 μg/kg, IV) in isoflurane-anesthetized rats. There were 12 rats in the vehicle group, and 3, 5 and 12 rats in the 25, 50 and 100 mg/kg Tempol-treated groups, respectively. Data presented are mean ± SEM. *p < 0.05, significant change. ^†P < T25, T50 and/or T100 vs. vehicle.

FIGURE 4

The changes in paw-withdrawal latency from baseline (BL) elicited by a bolus injection of fentanyl (25 μg/kg, IV) in conscious rats that had received an injection of vehicle (VEH) or Tempol (100 mg/kg, IV) 20 min previously. There were six rats in each group. The data are presented as mean ± SEM. *p < 0.05, significant from baseline. There were no differences between Vehicle- or Tempol-treated rats at any time point (p > 0.05, for all comparisons).