title: D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat.
abstract: Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D(1) receptor (D(1)R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D(1)R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 +/- 3.4 microg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO(2)), elevated end-tidal carbon dioxide (ETCO(2)), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 microg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D(1)R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO(2) and ETCO(2) to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 +/- 4.3 microg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D(1)R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.
authors.affiliation: The University of Wisconsin, Department of Physiology, Medical Sciences Center, 1300 Univ. Ave., Madison, WI 53706, USA. pmlalley@facstaff.wisc.edu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lalley
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002245:Carbon Dioxide; D002415:Cats; D018491:Dopamine Agonists / Q000494:pharmacology*; D004594:Electrophysiology; D045853:Exhalation; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects*; D010108:Oxyhemoglobins; D010507:Periodicity; D010617:Phenanthridines / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012119:Respiration / Q000187:drug effects*; D012137:Respiratory System / Q000294:innervation; D013990:Tidal Volume
chemical_list: D000701:Analgesics, Opioid; D001552:Benzazepines; D018491:Dopamine Agonists; D010108:Oxyhemoglobins; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; D002245:Carbon Dioxide; C061532:dihydrexidine; C071262:SK&F 82958; D005283:Fentanyl