Naunyn-Schmiedeberg's Arch Pharmacol (1995) 351:87-92 © Springer-Verlag 1995 Sabatino Maione • Juan Leyva • Mirella Pallotta • Liberato Berdno • Vito De Novellis • Francesco Rossi Involvement of opioid receptors in N-MethyI-D-aspartate-induced arterial hypertension in periaqueductal gray matter Received: 19 May 1994/Accepted: 21 September 1994 Abstract Arterial hypertension induced by microinjec- tions of N-methyl-D-aspartate (NMDA) (2 nmol/rat) in- to the midbrain periaqueductal gray matter was used to assess the involvement of opioid receptors (p, fi and K) in modulating pressor periaqueductal gray neurons. Groups (n = 5-8) of urethane-anaesthetised rats received, 5 min before NMDA, microinjections of selective opioid recep- tor antagonists in the periaqueductal gray area and arteri- al blood pressure was monitored. Pretreatments with naloxone (5 nmol/rat), a non selective p receptor antago- nist, or naltrindole hydrochloride (5 nmol/rat), a selective & receptor antagonist, significantly (P< 0.05) decreased by 31%0 and 37 %0, respectively, NMDA-induced hyperten- sion. The latency for the maximum increase of NMDA-in- duced hypertension was also significantly (P<0.05) in- creased with naloxone. Pretreatment with nor-binaltor- phimine (5 nmol/rat), a selective x receptor antagonist, only increased the latency of NMDA-induced hyperten- sion. Each opioid antagonist failed per se to alter arterial blood pressure. Microinjection of morphine (13 nmol/rat), a non selective/t receptor agonist, signifi- cantly decreased (P<0.05) by 57.5% NMDA-induced arterial hypertension and this effect was antagonised by naloxone. Combined pretreatments in the periaqueductal gray area with naloxone and the GABAA antagonist bicuculline (2.5 nmol/rat; 5 min before naloxone) anta- gonised the effect of naloxone on NMDA-induced hyper- tension. In contrast, bicuculline significantly (P<0.05) potentiated morphine-induced decrease of NMDA hyper- tension. Combined pretreatments in the periaqueductal gray area with naloxone and the glycine antagonist strychnine (8 nmol/rat; 5 min before naloxone) failed to prevent the effect of naloxone on the NMDA-induced car- diovascular changes. S. Malone (~) • J. Leyva • M. Pallotta • L. Berrino • V. De Novellis F. Rossi Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery, II University of Naples, Via Costantinopoli 16, 1-80138 Naples, Italy These data suggest that periaqueductal gray vasopres- sor neurons receive both direct opioid and GABAergic in- hibitory inputs. The latter may be, in turn, negatively modulated by opioid fibres mainly through p and fi sub- type receptors. Key words GABA • NMDA • Opioids Periaqueductal gray area Introduction Periaqueductal gray (PAG) matter anatomically repre- sents a relatively homogeneous midbrain neural density that wraps the aqueduct along its entire length. Currently such a midbrain region is defined as being made up of neural cell columns projecting along the aqueduct in a rostrocaudal direction (Bandler et al. 1991). Two features of this area have solicited interest among scientists: nociception control (Fardin et al. 1984; Hoso- buchi et al. 1979; Jensen and Yaksh 1992; Liebeskind et al. 1973; Oliv6ras and Besson 1988; Oliv6ras et al. 1974) and modulation of behavioural changes which are gener- ally defined as defensive behaviour (Bandler et al. 1985; Depaulis et al. 1989; Keay et al. 1990). Although there are controversial findings about the ef- fective role of endogenous opioids for analgesia induced by PAG-stimulation (Aimone and Gebhart 1987; Cannon et al. 1982), it is conceivable that p and tc opioid subtype receptors, mostly found within PAG matter (Kachaturian et al. 1985), have a role in modulating PAG-induced an- tinociception. More recent studies show that besides the above-men- tioned functions, PAG matter integrates two other impor- tant vital functions: cardiovascular and respiratory (Car- rive et al. 1987; Lovick 1986, 1987, 1992a). In fact, after the stimulation of neurons along dorsal or ventral col- umns a hypertensive or hypotensive effect is respectively generated, demonstrating a regional modulation of the vascular tone by PAG matter (Bandler et al. 1991; Lovick 1986, 1987). It has been demonstrated that descending fi-