Activation of opioid μ-receptors, but not δ- or κ-receptors, switches pulmonary C-fiber-mediated rapid shallow breathing into an apnea in anesthetized rats

Abstract

Rapid shallow breathing (RSB) is mainly mediated by bronchopulmonary C-fibers (PCFs). We asked whether this RSB could be modulated by opioids. In anesthetized rats right atrial bolus injection of phenylbiguanide (PBG) to evoke RSB was repeated after: (1) intravenously giving fentanyl (μ-receptor agonist), DPDPE (δ-receptor agonist), or U-50488H (κ-receptor agonist); (2) fentanyl (iv) following naloxone methiodide, a peripheral opioid receptor antagonist; (3) bilateral microinjection of fentanyl into the nodose ganglia; (4) fentanyl (iv) with pre-blocking histamine H(1) and H(2) receptors by diphenhydramine and ranitidine. Systemic fentanyl challenge, but not DPDPE or U-50488H, switched the PBG-induced RSB to a long lasting apnea. This switch was blocked by naloxone methiodide rather than diphenhydramine and ranitidine. After microinjecting fentanyl into the nodose ganglia, PBG also produced an apnea. Our results suggest that activating μ-receptors is capable of turning the PCF-mediated RSB into an apnea, at least partly, via facilitating PCFs' activity and this switching effect appears independent of the released histamine.

Fig 1

Fentanyl-induced changes in cardiorespiratory responses to PBG. A: A representative recording showing that fentanyl (FEN, 8 μg/kg, iv) converted the PBG (4.5 μg/kg)-induced RSB (left) into a long-lasting apnea (middle) and this facilitating effect disappeared 2 h later (right). The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B: Group data of the effects of FEN on the cardiorespiratory responses to PBG. N = 7; mean ± SE. Note: all the cardiorespiratory responses to PBG were significant (P < 0.01). * P < 0.05 and ** P < 0.01 compared with before fentanyl. T_E, expiratory duration; MBP, mean arterial blood pressure; HR, heart rate.

Fig 2

Opioid δ- (A) and κ-receptor agonist (B) failed to convert the PBG-induced RSB into an apnea. The top panes present representative recordings showing that fentanyl (FEN, 8 μg/kg, iv) failed to converted the PBG (4.5 μg/kg)-induced RSB into a apnea and the bottom panes are the corresponding group data. In the top panel, the traces are arterial blood pressure (BP) and tidal volume (V_T). N = 7 for each agonist; mean ± SE; Note:all the cardiorespiratory responses to PBG were significant (P < 0.01). T _E, expiratory duration; MBP, mean arterial blood pressure; and HR, heart rate.

Fig 3

A representative phrenic nerve recording showing that fentanyl (8 μg/kg, iv) turns the PBG (3 μg/kg)-induced RSB into an apnea without changing the tracheal pressure and the partial recovery from the apnea in a paralyzed and ventilated rat. The traces from the top to bottom are arterial blood pressure (ABP), tracheal pressure (Pt), phrenic nerve activity (PNA) and integrated PNA (iPNA).

Fig 4

The effect of peripheral opioid receptor antagonist naloxone methiodide (NXM) and fentanyl (FEN) on the cardiorespiratory responses to PBG. A, a representative recording showing that fentanyl (8 μg/kg, iv) failed to convert the PBG (6 μg/kg)-induced RSB into an apnea after NXM was administered. The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B, the corresponding group data. N = 6; mean ± SE. Note: all the cardiorespiratory responses to PBG were significant (P < 0.01). * P < 0.05 compared with before fentanyl. T_E, expiratory duration; MBP, mean arterial blood pressure; and HR, heart rate.

Fig 5

The effect of intra-nodose ganglia microinjection of fentanyl (FEN) on cardiorespiratory responses to PBG. A, a representative recording showing that fentanyl microinjected into the nodose ganglia converted the PBG (4.5 μg/kg)-induced RSB into an apnea. The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B, the corresponding group data. N = 6; mean ± SE. Note: all the cardiorespiratory responses to PBG were significant (P < 0.01). ** P < 0.01 compared with before fentanyl. T_E, expiratory duration; MBP, mean arterial blood pressure; and HR, heart rate.

Fig 6

The effect of fentanyl (FEN) on cardiorespiratory responses to PBG after blocking histamine H₁ and H₂ receptors. A, a representative recording showing that fentanyl still converted the PBG (4.5 μg/kg)-induced RSB into an apnea after the blockage of histamine H₁ and H₂ receptors by diphenhydramine and ranitidine (DPH/RTD). The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B, the corresponding group data. N = 7; mean ± SE. Note: all the cardiorespiratory responses to PBG were significant (P < 0.01). * P < 0.05 and ** P < 0.01 compared with before fentanyl. HR, heart rate; MBP, mean arterial blood pressure; T_E, expiratory duration.