Contribution of central μ-receptors to switching pulmonary C-fibers-mediated rapid shallow breathing into an apnea by fentanyl in anesthetized rats

Abstract

Our previous study has shown that activating peripheral μ-receptors is necessary for switching the bronchopulmonary C-fibers (PCFs)-mediated rapid shallow breathing (RSB) into an apnea by systemic administration of fentanyl. The brainstem nuclei, such as the medial nucleus tractus solitarius (mNTS) and the pre-Botzinger complex (PBC), are required for completing the PCF-mediated respiratory reflexes. Moreover, these areas contain abundant μ-receptors and their activation prolongs expiratory duration (T(E)). Thus, we asked if central μ-receptors, especially those in the mNTS and PBC, are involved in fully expressing this RSB-apnea switch by fentanyl. In anesthetized rats, the cardiorespiratory responses to right atrial injection of phenylbiguanide (PBG, 3-6μg/kg) were repeated after: (1) fentanyl (iv), a μ-receptor agonist, alone (8μg/kg, iv); (2) fentanyl following microinjection of naloxone methiodide (NXM, an opioid receptor antagonist) into the cisterna magna (10μg/4μl); (3) the bilateral mNTS (10mM, 20nl); or (4) PBC (10mM, 20nl). Our results showed that PBG shortened T(E) by 37±6% (RSB, from 0.41±0.05 to 0.26±0.03s, P<0.01), but it markedly prolonged T(E) by 5.8-fold (an apnea, from 0.50±0.04s to 2.9±0.57s, P<0.01) after fentanyl (iv). Pretreatment with NXM injected into the cisterna magna or the PBC, but not the mNTS, prevented the fentanyl-induced switch. This study, along with our previous results mentioned above, suggests that although peripheral μ-receptors are essential for triggering the fentanyl-induced switch, central μ-receptors, especially those in the PBC, are required to fully exhibit such switch.

Summary statement: Our results suggest that the activation of central μ-receptors, especially those in the pre-Botzinger complex, is required for switching the pulmonary C-fiber-mediated rapid shallow breathing into an apnea by systemic administration of fentanyl.

Fig. 1

Fentanyl-induced changes in cardiorespiratory responses to phenylbiguanide (PBG). A: A representative recording showing that fentanyl (FEN, 8 μg/kg, iv) converted the PBG-induced RSB (left) into a long-lasting apnea (middle) and this converting effect declined 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 comparing the cardiorespiratory responses to PBG before and after FEN. N = 6; mean ± SE. Note: in B, 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

Intracisternal injection of naloxone methiodide (NXM) prevents fentanyl (FEN)-induced switch. A: A representative recording showing the cardiorespiratory response to PBG before (right) and after (left) FEN following intracisternal injection of NXM. The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B: Group data showing the effects of FEN on the cardiorespiratory responses to PBG. N = 6; mean ± SE. Note: in B, 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; HR, heart rate.

Fig. 3

Microinjection of naloxone methiodide (NXM) into the medial nucleus tractus solitarius (mNTS) does not prevent the fentanyl (FEN)-induced the switching of phenylbiguanide (PBG)-induced RSB into an apnea. A: A representative recording showing the cardiorespiratory response to PBG before (right) and after (left) FEN following intra-mNTS injection of NXM. The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B: Group data showing FEN impact on the cardiorespiratory responses to PBG before and after intra-mNTS injection of NXM. N = 6; mean ± SE. Note: in B, 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. C: A representative slice containing the mNTS, in which the injection locations are stained by fluorescence microbeads (red). AP, area postrema; CC, central canal; NTS, the nucleus of the solitary tract; Gr, gracile nucleus; 12N, hypoglossal nucleus.

Fig. 4

Microinjection of naloxone methiodide (NXM) into pre-Botzinger (PBC) prevents the fentanyl (FEN)-induced switch. A: A representative recording showing the cardiorespiratory response to PBG before (right) and after (left) FEN following intra-PBC injection of NXM. The traces from the top to bottom are arterial blood pressure (BP) and tidal volume (V_T). B: Group data showing FEN impact on the cardiorespiratory responses to PBG before and after intra-PBC injection of NXM. N = 6; mean ± SE. Note: in B, 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; HR, heart rate. C: A representative slice containing the PBC, in which the injection locations are stained by fluorescence microbeads (red). Amb, ambiguus nucleus; Gi, gigantocellular reticular nucleus; IO, inferior olive nucleus; IRt, intermediate reticular nucleus; NTS, nucleus of the solitary tract; PBC, pre-Botzinger complex; PCRt, parvicellular reticular nucleus; pv, pyramidal tract; ROb, raphe obscurus nucleus; VN, vestibular nucleus; Sp5I, spinal 5 nucleus, interpolar part.