The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing.
Inhibitors of nitric oxide synthase (NOS) have analgesic properties and reduce opioid tolerance and dependency. To investigate a possible interaction of NOS inhibitors with the respiratory depressant action of morphine, we determined the effects of the neuronal NOS inhibitor 7-nitroindazole (7-NI) on the ventilatory carbon dioxide response curve; subsequently, we studied the effects of additional morphine application. Finally, using naloxone, we investigated a possible interaction (at the opioid receptor) between the effects of 7-NI and morphine. The effects of 7-NI 50 mg kg-1 i.p., morphine 0.1 mg kg-1 i.v. and naloxone 0.1 mg kg-1 i.v. were studied using dynamic end-tidal carbon dioxide forcing in eight cats under alpha-choralose-urethane anaesthesia. Data analysis was performed using a two-compartment model comprising a fast peripheral and a slow central component characterized by carbon dioxide sensitivities and a single offset B (apnoeic threshold). 7-NI decreased the mean apnoeic threshold from 4.27 (SD 0.87) to 2.59 (1.71) kPa. Peripheral and central carbon dioxide sensitivities were reduced from 0.56 (0.22) to 0.26 (0.09) litre min-1 kPa-1 and from 0.09 (0.05) to 0.04 (0.03) litre min-1 kPa-1, respectively. Morphine increased the apnoeic threshold by 0.5 kPa and reduced carbon dioxide sensitivity by a further 35%. Naloxone reversed the ventilatory effects of morphine but not those induced by 7-NI. We conclude that the respiratory effects of 7-NI and morphine are mediated independently and that the effects of 7-NI do not result from interaction with opioid receptors.
Teppema
L
L
Department of Physiology, Leiden University Medical Centre, The Netherlands.
Sarton
E
E
Dahan
A
A
Olievier
C N
CN
D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000502:physiology; D002415:Cats; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D012119:Respiration / Q000187:drug effects*
D000700:Analgesics; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007191:Indazoles; D002245:Carbon Dioxide; D009020:Morphine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole