8-OH-DPAT abolishes the pulmonary C-fiber-mediated apneic response to fentanyl largely via acting on 5HT1A receptors in the nucleus tractus solitarius

Abstract

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT(1A)Rs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT(1A)Rs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT(1A)Rs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT(1A)R agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT(1A)R antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, T(E)), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT(1A)Rs.

Fig. 1.

A: typical recordings showing the fentanyl-evoked cardiorespiratory activities and their recoveries. f_R, respiratory frequency; V_E, minute ventilation. B: typical recordings showing the fentanyl-evoked apneic and cardiovascular responses before (CON) and after perineural treatment of the vagi with capsaicin (pCAP) and subsequent bivagotomy in an anesthetized rat. C: typical recordings of the cardiorespiratory responses to fentanyl before and after perineural treatment of the vagi with vehicle for twice (pVEH1 and pVEH2) in another rat. The traces are arterial blood pressure (ABP), heart rate (HR), and tidal volume (V_T). Arrows point to the onset of bolus injection of fentanyl (5.0 μg/kg) into the right atrium.

Fig. 2.

Group data of the fentanyl-evoked expiratory duration (T_E) prolongation and cardiovascular responses before and after perineural treatment of the vagi with capsaicin (pCAP) and subsequent bivagotomy (A, n = 7) or after twice perineural treatments of the vagi with vehicle (pVEH1 and pVEH2; B, n = 6). Values are means ± SE; **P < 0.01, compared with the baseline values (before injecting fentanyl into the right atrium); ‡P < 0.01, compared with control (CON = without manipulation of vagi). MABP, mean arterial blood pressure.

Fig. 3.

Baseline cardiorespiratory activities (CON) and their responses to systemic 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) challenge (DPAT). n = 9; values are means ± SE; *P < 0.05 and **P < 0.01, vs. CON.

Fig. 4.

Fentanyl-induced T_E prolongation and cardiovascular responses before and after intravenous administration of DPAT (A) or vehicle (VEH, B). n = 9; values are means ± SE; *P < 0.05 and **P < 0.01, compared with the baseline values (before injecting fentanyl into the right atrium); ‡P < 0.01, compared with CON (before systemic DPAT challenge).

Fig. 5.

Fentanyl-evoked T_E prolongation before and after intra-caudomedial nucleus of solitary tract (mNTS) microinjection of DPAT without and with local WAY-100635 pretreatment (WAY+DPAT). A: typical recordings with arrows indicating the onset of bolus injections of fentanyl via the right atrium. B: group data. n = 7; values are means ± SE; **P < 0.01, compared with baseline values (“0”) obtained before injecting fentanyl into the right atrium; †P < 0.05 and ‡P < 0.01, compared with control (CON = without systemic or local treatment) or WAY+DPAT. C: bilateral microinjection locations labeled by fluorescent microbeads. 10N, dorsal motor nucleus of vagus; 12N, hypoglossal nucleus; CC, central canal; Gr, gracile nucleus.

Fig. 6.

Typical recordings showing the effects of microinjecting WAY into the mNTS (A) or the interstitial NTS (iNTS, B) on the apneic blockade by systemic DPAT challenge in two rats, respectively. VEH, local microinjection of vehicle; VEH+DPAT or WAY+DPAT, local microinjection of vehicle or WAY followed by systemic DPAT challenge. Arrows point to the onset of bolus injection of fentanyl into the right atrium. C: locations of microbeads microinjected into bilateral iNTS.

Fig. 7.

Effects of microinjection of WAY into the mNTS (A) or the iNTS (B) on the apneic blockade by systemic DPAT challenge. CON1, the control of apneic response to fentanyl before systemic DPAT challenge; CON2, the recovery of the apneic response from systemic DPAT challenge; DPAT, intravenous injection of 8-OH-DPAT; WAY+ DPAT, intra-mNTS or -iNTS microinjection of WAY-100635 (WAY) followed by systemic DPAT challenge. n = 8; values are means ± SE; *P < 0.05 and **P < 0.01, compared with the baseline values (before injecting fentanyl into the right atrium); †P < 0.05 and ‡P < 0.01, compared with CON1/CON2 and DPAT.

Fig. 8.

Comparison of baseline cardiorespiratory activities and their responses to systemic DPAT challenge before and after pretreating the mNTS with WAY. CON, before intra-mNTS injection of WAY; DPAT, systemic DPAT challenge; WAY, intra-mNTS injection of WAY; WAY+DPAT, intra-mNTS injection of WAY followed by systemic DPAT challenge. n = 8; values are means ± SE; *P < 0.05 and **P < 0.01, compared with CON; †P < 0.05 and ‡P < 0.01, compared with WAY. Note: all data of WAY+DPAT are not significantly different from those of DPAT alone (P > 0.05). Pet_CO2, end-tidal pressure of carbon dioxide.