Differential cardiovascular and respiratory responses to central administration of selective opioid agonists in conscious rabbits: correlation with receptor distribution

1 The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of a range of doses (0.01, 0.1 and 1.0 nmol kg−1) of specific μ‐ δ‐ and κ‐opioid agonists on cardiovascular and respiratory function and on plasma catecholamines have been studied in conscious rabbits. The dis...

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Published inBritish journal of pharmacology Vol. 98; no. 3; pp. 903 - 913
Main Authors May, C.N., Dashwood, M.R., Whitehead, C.J., Mathias, C.J.
Format Journal Article
LanguageEnglish
Published Oxford, UK Blackwell Publishing Ltd 01.11.1989
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Summary:1 The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of a range of doses (0.01, 0.1 and 1.0 nmol kg−1) of specific μ‐ δ‐ and κ‐opioid agonists on cardiovascular and respiratory function and on plasma catecholamines have been studied in conscious rabbits. The distribution of μ‐ δ‐ and κ‐opioid receptors was localized in rabbit brain by in vitro autoradiography. 2 The μ‐agonist [D‐Ala2, MePhe4‐Gly5‐ol]enkephalin (DAGOL) given i.c.v. caused a large rise in plasma noradrenaline and adrenaline, hypertension accompanied by an initial bradycardia followed by tachycardia, respiratory depression and sedation. After i.c. administration there were similar changes in heart rate (HR) and respiration, but no significant changes in mean arterial pressure (MAP) or plasma catecholamines. 3 The δ‐agonist [D‐Pen2,5]enkephalin (DPDPE) increased MAP and HR after both i.c.v. and i.c. administration, caused a small increase in noradrenaline but had no effect on adrenaline and did not alter respiration rate or blood gases. After i.c.v. DPDPE the rabbits became more alert and active. 4 The κ‐agonist U69593 given i.c.v. or i.c. had no effect on MAP or HR. After i.c.v. U69593, Paco2 fell, but there were no other respiratory effects. The responses to dynorphin 1–13, an endogenous κ‐agonist, were similar to those of U69593. 5 The opioid antagonist naloxone (30 nmol kg−1) given intravenously (i.v.) blocked the effects of i.c.v. DAGOL (1 nmol kg−1). A 100 fold higher dose of i.v. naloxone (3 μmol kg−1) was required to abolish the effects of i.c.v. DPDPE (1 nmol kg−1). 6 Autoradiographic studies demonstrated a high density of μ‐ and δ‐opioid receptors in hypothalamic sites. In the brainstem μ‐receptors were demonstrated in the nucleus tractus solitarius (NTS) and δ‐receptors in the dorsal motor nucleus of the vagus. κ‐Receptors were not detected in either the hypothalamus or brainstem. 7 These findings demonstrate that DAGOL increases sympatho‐adrenal outflow, probably by stimulation of hypothalamic μ‐receptors. The effects on HR are probably partly through a baroreflex and partly through an action of DAGOL on μ‐receptors in the dorsal motor nucleus of the vagus. DPDPE probably acts on δ‐receptors in the NTS to increase MAP and HR. Respiratory depression resulted from stimulation of μ‐receptors in the brainstem with no evidence of δ‐ or κ‐receptors being involved.
Bibliography:Howard Florey Institute of Physiology and Medicine, University of Melbourne, Parkville 3052, Victoria, Australia.
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ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.1989.tb14620.x