Levels of endogenous opioids are increased in morbidly obese humans and obese rats. Endogenous opioids are important neuromodulators, and are involved in a wide range of functions including ventilatory control. We studied eight lean and eight obese Zucker (Z) rats at 6 and 16 wk of age. We assessed minute ventilation (V E) at rest and during hypercapnic challenges, as well as peak oxygen consumption (V O(2peak)) after the administration of saline (control), naloxone hydrochloride (N(HCl)), and naloxone methiodide (N(M)). Administration of N(HCl) and N(M) to lean animals had no effect on V E and V O(2peak). Similarly, N(M) failed to alter V E and V O(2peak) in obese rats studied at 6 or 16 wk of age. In young obese rats, N(HCl) significantly (p < 0.05) increased resting V E (721 +/- 154 [mean +/- SD] ml/kg/min versus 937 +/- 207 ml/kg/min, saline versus N(HCl), respectively); VE in response to 4% CO(2) (924 +/- 110 ml/kg/min versus 1,212 +/- 172 ml/ kg/min); V E in response to 8% CO(2) (1,233 +/- 172 ml/kg/min versus 1,565 +/- 327 ml/kg/min); and V O(2peak) (90.8 +/- 9.6 ml/kg(0.75)/min versus 98.3 +/- 5.9 ml/kg(0.75)/min). However, N(HCl) administration had no effect on V E or V O(2peak) in obese rats retested at 16 wk of age. Thus, endogenous opioids modulate resting ventilation, ventilatory responsiveness to CO(2), and V O(2peak) in young obese rats by acting specifically on receptors located within the central nervous system. This modulation disappears once the animals reach 16 wk of age.
BACKGROUND: Ventilation in response to hypoxia is reduced in some obese humans and is believed to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS). Ventilation in response to hypoxic exposure is closely related to the release of excitatory neurotransmitters, in particular glutamate, acting speci®cally on N-methyl-D-aspartate (NMDA) receptors. OBJECTIVES: The aim of the present study was to investigate whether NMDA receptor-mediated mechanisms are responsible for the altered ventilatory response to sustained hypoxia observed in obese Zucker (Z) rats. SUBJECTS: Seven lean and seven 15-week-old obese male Z rats were studied. MEASUREMENTS: Ventilation (V Ç E ) at rest and during 30 min sustained hypoxic (10% O 2 ) exposure was measured by the barometric method. V Ç E was assessed following the blinded-random administration of equal volumes of either saline (vehicle) or dextromethorphan (DM, 10 mgakg), a non-competitive glutamate NMDA receptor antagonist. RESULTS: DM had no effects on resting V Ç E in both lean and obese rats during room air breathing. Lean rats treated with DM exhibited a signi®cant (P`0.05) depression in V Ç E , V T , and V T aT I during either the early (5 min) or the late phase (30 min) of ventilatory response to sustained hypoxia. In contrast, DM administration in obese rats did not change V Ç E , V T , or V T aT I during the early phase of ventilatory response to hypoxia. During the late phase of ventilatory response to hypoxia. obese rats treated with DM exhibited a similar depression in V Ç E and V T as observed in lean rats, but had no signi®cant change in V T aT I during the 30 min hypoxic exposure. CONCLUSION: Our ®ndings indicate that altered glutamatergic mechanisms acting on NMDA receptors are partially responsible for a blunted early phase of ventilatory response to hypoxia noted in obese rats and also contribute to their reduced neural respiratory drive.
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