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Cardiorespiratory effects of the novel opioid analgesic HP 736 in the anesthetized dog and conscious goat. J Pharmacol Exp Ther 1992 Mar;260(3):1268-77

Date

03/01/1992

Pubmed ID

1347566

Scopus ID

2-s2.0-0026650839   3 Citations

Abstract

7-Bromo-(3a,5-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-pyrrolo[2,3- 6]indol-5-ol fumarate (HP 736) is a novel opioid analgesic. In vitro, HP 736 displaces [3H]dihydromorphine (IC50 = 8.3 x 10(-10) M) and [3H]bremazocine (IC50 = 7.4 x 10(-8) M) from mu and kappa opioid receptors, respectively, and displays modest acetylcholinesterase inhibitory activity (IC50 = 4.0 x 10(-5) M). The in vivo antinociceptive activity of HP 736 was found to be comparable to morphine in the modified Haffner's tail clip assay in mice and the D'Amour-Smith tail flick assay in rats. Moreover, these analgesic effects were found to be completely antagonized by the administration of the narcotic antagonist naloxone. A major liability of opioid analgesics such as morphine is the potential to cause cardiorespiratory depression. HP 736 (2, 4 and 10 mg/kg, i.v.) was found to cause significantly less respiratory depression in the anesthetized dog when compared to equivalent doses of morphine. At 10 mg/kg, morphine caused a 48% reduction in arterial oxygen partial pressure (PaO2) (-42.3 +/- 2.5 mm Hg) and a 52% increase in arterial carbon dioxide partial pressure (PaCO2) (21.0 +/- 3.4 mm Hg). In contrast, the same dose of HP 736 produced no significant decrease in PaO2, but did cause a slight 19% increase in PaCO2 (8.2 +/- 1.3 mm Hg), which was significantly less than the response seen after morphine treatment. It was found that pretreatment of the dogs with atropine sulfate (1 mg/kg, i.v.) "unmasked" the respiratory depressant activity of HP 736 (2 mg/kg, i.v.), indicating that the acetylcholinesterase inhibitory activity of the compound may contribute to its reduced cardiorespiratory liability. Finally, in confirmatory experiments conducted in conscious goats, HP 736 (0.5 mg/kg, i.v.) was found to stimulate pulmonary ventilation, increase PaO2 and oxygen consumption (+40%) and decrease PaCO2 with an overall stimulatory effect on the metabolic rate. In contrast, the same dose of morphine decreased metabolic rate, reduced pulmonary ventilation (-20%) and PaO2 and increased PaCO2. Overall, the results of these studies indicate that HP 736 is a potent opioid analgesic which appears to lack significant cardiorespiratory depressant activity.

Author List

Hubbard JW, Locke KW, Forster HV, Brice AG, Pan LG, Lowry TF, Forster AM, Forster MA, Cornfeldt M, Vanselous CL

Author

Hubert V. Forster PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Analgesics, Opioid
Animals
Atropine
Carbon Dioxide
Dogs
Female
Goats
Hemodynamics
In Vitro Techniques
Indoles
Male
Mice
Morphine
Oxygen
Pyrroles
Rats
Rats, Inbred Strains
Respiration
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75