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. 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. 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. 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. 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). 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. 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.

1. In conscious rabbits, intravenous morphine caused hypertension, bradycardia, hyperglycaemia and increased plasma adrenaline and noradrenaline. These effects were prevented by ganglionic blockade with pentolinium. 2. The cardiovascular responses to morphine were not altered by pretreatment with a vasopressin V1-receptor antagonist. 3. After bilateral adrenalectomy morphine caused a similar rise in noradrenaline but no increase in adrenaline. The rise in blood pressure was attenuated and the hyperglycaemia was abolished. 4. Adrenaline infused intravenously to mimic the levels that occurred after morphine caused a similar degree of hyperglycaemia but only a small increase in blood pressure. 5. Pretreatment with intracerebroventricular naloxone prevented the morphine-induced hypertension, hyperglycaemia, increase in plasma catecholamines, respiratory depression and sedation. 6. These results demonstrate that, in conscious rabbits, intravenous morphine causes hypertension by increasing sympathetic vasoconstrictor nerve activity and elevating plasma adrenaline levels; the latter alone produces the hyperglycaemia. Vasopressin release is not involved in the hypertensive response to morphine. The effects of morphine appear to result from stimulation of central opiate receptors leading to enhanced sympathoadrenal outflow.

1 In conscious rabbits intracerebroventricular (i.c.v.) morphine (10 and 50pgkg-1) caused a doserelated increase in plasma noradrenaline and adrenaline, respiratory depression and sedation. The increase in sympatho-adrenal outflow resulted in hypertension accompanied by bradycardia and the increase in adrenaline secretion caused hyperglycaemia. Morphine (1 mg kgt i.c.v.) and i.c.v. saline had no effect. 2 The same doses of morphine given intracisternally (i.c.) caused bradycardia and a similar degree of respiratory depression to i.c.v. morphine, but no significant increase in blood pressure and only a small, gradual rise in plasma adrenaline. 3 Intravenous naloxone (1 mgkg-) did not block the hypertension, hyperglycaemia or increase in plasma catecholamines that followed i.c.v. morphine, but prevented the respiratory depression and sedation. 4 Ganglionic blockade with pentolinium prevented the rise in plasma catecholamines, blood pressure and plasma glucose induced by i.c.v. morphine. 5 These findings demonstrate that the increased sympathoadrenal outflow following i.c.v. morphine results from an action on periventricular structures. The resultant increase in plasma catecholamines, which is largely naloxone resistant, accounts for the hypertension and hyperglycaemia. The bradycardia is probably partly baroflex mediated and partly due to an increase in vagal tone as a result of stimulation of brainstem opioid receptors. The respiratory depression is probably due to an action of morphine on brainstem opioid receptors.

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The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of β‐endorphin (0.01, 0.1 and 1.0 nmol kg−1) were examined in conscious rabbits. After i.c.v. β‐endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in Paco2 and fall in Pao2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg−1). A combination of prazosin (2 mg kg−1) and yohimbine (1 mg kg−1), given i.v., prevented the rise in MAP induced by i.c.v. β‐endorphin. After i.c. β‐endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression. Clonidine (1.0 μg kg−1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 μmol kg−1). These results demonstrate that β‐endorphin acts centrally, probably mainly on periventricular μ‐opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to α‐adrenoceptor‐mediated vasoconstriction. The respiratory depression is probably mediated by brainstem μ‐receptors. A role for β‐endorphin in the central hypotensive action of α2‐adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.