Elsevier

Brain Research

Volume 762, Issues 1–2, 11 July 1997, Pages 61-71
Brain Research

Research report
Cardiovascular effects of microinjections of opioid agonists into the `Depressor Region' of the ventrolateral periaqueductal gray region

https://doi.org/10.1016/S0006-8993(97)00285-0Get rights and content

Abstract

Microinjections of excitatory amino acids made into the ventrolateral midbrain periaqueductal gray of the rat have revealed that neurons in this region integrate a reaction characterised by quiescence, hyporeactivity, hypotension and bradycardia. Microinjections of both excitatory amino acids and opioids into the ventrolateral periaqueductal gray have shown also that it is a key central site mediating analgesia. The effects of injections of opioids into the ventrolateral periaqueductal gray on arterial pressure and heart rate or behaviour are unknown. In this study we first mapped in the rat the extent of the ventrolateral periaqueductal gray hypotensive region as revealed by microinjections of excitatory amino acids. We found that ventrolateral periaqueductal gray depressor region extended more rostrally than previously thought into the tegmentum ventrolateral to the periaqueductal gray. Subsequently we studied for the first time, the effects of microinjections of μ-, δ-, and κ-opioid agonists made into the ventrolateral periaqueductal grey depressor region. In contrast to the effects of excitatory amino acid injections, microinjections of the μ-opioid agonist ([d-Ala2,N-Me-Phe4,Gly-ol5]enkephalin) evoked hypertension and tachycardia at approximately 50% of sites. Similar to excitatory amino acid injections, microinjections of both the δ-opioid agonist ([d-Pen2,d-Pen5]enkephalin), and the κ-opioid agonist ((5,7,8)-(+)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide) evoked either a hypotension and bradycardia, or had no effect. These results indicate that different opiate receptor subtypes are present on a distinct population of ventrolateral periaqueductal gray neurons, or at different ventrolateral periaqueductal gray synaptic locations (pre- or post-synaptic).

Introduction

The columnar organization of the midbrain periaqueductal gray region (PAG) is now well established 1, 2, 3, 6. The column of cells lying lateral to the midbrain aqueduct [lPAG] has received most attention, with behaviour, cardiovascular changes and connectivities of the lPAG region having been extensively studied. In contrast, the ventrolateral PAG [vlPAG] has been studied primarily with respect to its analgesic properties. Thus, Reynolds first reported in 1969 that electrical stimulation of the vlPAG evoked antinociception [57], a phenomenon studied by many others 22, 26, 39, 44, 45, 52, 53. Microinjection of excitatory amino acids into the same region subsequently demonstrated that the antinociception was mediated by activation of neurons within the vlPAG 4, 12, 33, 34, 35, 63. The vlPAG is also a key site at which opiates act centrally to produce analgesia 33, 42, 51, 60, 68and it has been found further that vlPAG-evoked analgesia is mediated by both μ- and δ-receptor mechanisms 9, 33, 58, 59.

Recently, attention has focussed on the behavioural and cardiovascular responses mediated by the vlPAG. Thus, excitation of vlPAG neurons by microinjections of the excitatory amino acid, d,l-homocysteate (DLH), evokes significant falls in both arterial pressure and heart rate 11, 27, 46, 48. Furthermore, microinjections of excitatory amino acids into the vlPAG in the freely moving animal evokes behavioural changes characterised by quiescence and hyporeactivity 1, 2, 3, 20, 73. Overall this reaction of quiesence, hyporeactivity, hypotension and bradycardia bears a striking resemblance to the `shock-like', passive emotional coping style of response associated with injury-evoked blood loss and deep pain 2, 3, 7, 21, 23, 30, 38, 40, 41, 46, 67.

Although the pivotal role of opioids in mediating vlPAG-evoked analgesia is well established, the effects of opiate agonists on either the cardiovascular or behavioural responses mediated by the vlPAG have not been systematically investigated. As a first step we examined the effects on arterial pressure and heart rate of microinjections of opiate agonists into the vlPAG. In order to establish that the opioid microinjections were made within the `hypotensive portion' of the vlPAG a systematic mapping study using microinjections of DLH was first undertaken.

Section snippets

Anaesthesia and surgery

Experiments were performed on 72 halothane (1.5% in 100% oxygen) anaesthetised male Sprague-Dawley rats (240–350 g). A saline (0.9%) filled polyethylene catheter was placed in the left femoral artery (n=22) or left common carotid artery (n=50) for recording arterial pressure. In thirteen of these animals a second catheter was placed in the left femoral vein for the administration of the opioid antagonist naloxone (see below). The temperature of each rat was maintained at 37°C using an infrared

DLH-mapping experiments

Microinjections of DLH were made at a total of 333 sites (in 68 rats) within and adjacent to the PAG extending between A2.2 and A0.2 [56]. Mean resting arterial pressure and heart rate in the animals in these experiments were 103±2 mmHg and 361±5 bpm respectively. Injections into 164 sites (49%) evoked substantial falls in arterial pressure (mean fall 19±1%, range 6–45%), the decreases in arterial pressure usually being accompanied by a moderate bradycardia (mean decrease 26±2 bpm, range 7–65

Discussion

The discussion focusses on two main issues arising from these data. The first is the delineation of a `depressor' column within the caudal midbrain, and the second is the finding that actions at different opiate receptors within the caudal midbrain depressor column differentially modulate arterial pressure and heart rate.

Acknowledgements

This work was supported by grants to R.B. and K.A.K., and to R.B., MacD.J.C. and C.W. Vaughan from the NHMRC (Australia), and to R.B. and K.A.K. from the Clive and Vera Ramaciotti Research Foundation. We thank Alison Chiu, Clair Sorenson and Brent Gordon for their assistance in some of the experiments reported here. We thank Mr Clive Jeffrey and Roland Smith for photographic help.

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