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

Abstract

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.

Effects of μ‐opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits

“…Within this region lies the nucleus tractus solitarii, an important relay station for afferents from both arterial baroreceptors and cardiac receptors (Jordan & Spyer, 1986). Recent work has shown that, in the rabbit, there is a dense population of 5-binding sites within this nucleus (May et al, 1989a). It is not so clear where pu-agonists, injected into the 4th ventricle, might act to prevent circulatory decompensation during simulated haemorrhage.…”

“…In the rabbit, p-binding sites have been found in areas adjacent to the nucleus tractus solitarii (May et al, 1989a). The cardiovascular actions of intravenous morphine were always associated with respiratory depression, whereas the corresponding actions of 4th ventricular DAMGO were not.…”

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

“…In addition, chronic stimulation of OR induces tolerance and physical dependence (Cowan et al, 1988). By contrast, drugs acting on ␦OR produce more limited analgesia, but also give rise to considerably less undesirable side-effects and induce virtually no tolerance (Porreca et al, 1984;May et al, 1989; Sheldon et al, 1990;Szeto et al, 1999;Gallantine and Meert, 2005). For these reasons, ␦OR agonists have been proposed as possible alternatives to OR agonists for the treatment of chronic pain, including neuropathic (Mika et al, 2001;Petrillo et al, 2003;Morinville et al, 2004a) and chronic inflammatory pain (Desmeules et al, 1993;Stewart and Hammond, 1994;Fraser et al, 2000;Hurley and Hammond, 2000;Qiu et al, 2000;Cahill et al, 2003;Petrillo et al, 2003).…”

The effects of naloxone on the cardiovascular and respiratory effects of centrally administered corticotrophin releasing factor in conscious rabbits

“…The doses of naloxone were also higher than those which reversed the effects of centrally administered u-and S-opioid agonists in conscious rabbits (May et al, 1989a). Thus, the present findings suggest that in the rabbit, in contrast to the rat, the rise in blood pressure and increase in behavioural activity following i.c.v.…”

“…and intracisternal (i.c. ) administration of the selective 6-opioid agonist 5] enkephalin (DPDPE) raised blood pressure and heart rate (HR) and increased behavioural activity (May et al, 1989a). This finding raised the possibility that the effects of CRF may be mediated by release of endogenous opioid peptides that act on 5-opioid receptors.…”