8-OH-DPAT abolishes the pulmonary C-fiber-mediated apneic response to fentanyl largely via acting on 5HT1A receptors in the nucleus tractus solitarius.
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.
Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
Jianguo
J
Zhuang
Zhenxiong
Z
Zhang
Cancan
C
Zhang
Fadi
F
Xu
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001049:Apnea / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D005283:Fentanyl / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism
D009294:Narcotics; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005283:Fentanyl