Activating mNTS 5HT receptors eliminates the immediate apneic response to intravenous injection of fentanyl in anesthetized rats

Morphine is a commonly used analgesic with the most adverse side effect on depressing ventilation. Intravenous administration of 5HT 1A receptor agonist 8‐OH‐DPAT could eliminate the morphine‐induced apnea in rats, but the relevant mechanisms are not fully understood. Previous reports have shown that morphine is able to evoke a vagal‐mediated apnea via activating opioid μ‐receptors on bronchopulmonary C‐fibers (PCFs) and the caudal middle portion of nucleus tractus solitarius (mNTS) receiving dominant inputs from PCFs densely expresses 5HT 1A receptors in rats. Thus, we tested whether activation of 5HT, especially 5HT 1A , receptors in the mNTS would reduce the vagal‐mediated apneic response to fentanyl, an opioid μ‐receptor agonist, in anesthetized rats. Our results showed that: 1) bolus injection of fentanyl (5.0 μg/kg, iv.) evoked an immediate apnea (2.5 ± 0.5 s, 7‐fold prolongation of control T E ), which was fully dependent on vagus nerves; 2) this apneic response was abolished by mNTS microinjection of 5HT (2 nmol, 20 nl) or almost abolished by local 5HT 1A receptor activator 8‐OH‐DPAT (0.4 nmol, 20 nl); 3) this 5HT modulatory effect was prevented by pre‐treating the mNTS with 5HT 1 receptor antagonist propranolol (0.4 nmol, 20 nl). We conclude that activation of 5HT 1A receptors in the mNTS is capable of greatly suppressing or even blocking the vagal‐mediated apneic response to morphine in anesthetized rats.