Anandamide content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition

Abstract

Cannabinoids have been shown to modulate central autonomic regulation and baroreflex control of blood pressure (BP). The presence of cannabinoid CB(1) receptors on fibers in the nucleus tractus solitarius (NTS) suggests that some presynaptic modulation of transmitter release could occur in this region, which receives direct afferent projections from arterial baroreceptors and cardiac mechanoreceptors. This study, therefore, was performed to determine the mechanism(s) of effects of microinjection of an endocannabinoid, arachidonylethanolamide (anandamide, AEA), into the NTS on baroreflex sympathetic nerve responses produced by phenylephrine-induced pressure changes in anesthetized rats. AEA prolonged reflex inhibition of renal sympathetic nerve activity (RSNA), suggesting an increase in baroreflex sensitivity. This effect of AEA was blocked by prior microinjection of SR-141716 to block cannabinoid CB(1) receptors. To determine whether this baroreflex enhancement by AEA involved a GABA(A) mechanism, the baroreflex response to AEA was tested after prior blockade of postsynaptic GABA(A) receptors by bicuculline, which would eliminate any effects due to modulation of GABA activity. After bicuculline, which alone prolonged the baroreflex inhibition of RSNA, AEA shortened the duration of RSNA inhibition, suggesting a possible presynaptic inhibition of glutamate release previously obscured by a more dominant GABA(A) effect. To support a possible physiological role for AEA, AEA concentration in the NTS was measured after a phenylephrine-induced increase in BP. AEA content in the NTS was increased significantly over that in normotensive animals. These results support the hypothesis that AEA content is increased by brief periods of hypertension and suggest that AEA can modulate the baroreflex through activation of CB(1) receptors within the NTS, possibly modulating effectiveness of GABA and/or glutamate neurotransmission.

The complexities of the cardiovascular actions of cannabinoids

“…Although the role, if any, of endocannabinoids in cardiovascular regulation remains to be established, Rademacher et al (2003) reported that SR141716A injected into the nucleus tractus solitarius delayed baroreflex recovery in anaesthetised dogs, with the implication that endocannabinoids might play a role in this regulatory system. Furthermore, in the rat, injection of anandamide into the nucleus tractus solitarius increased baroreflex sensitivity in an SR147116A-sensitive manner, possibly via modulation of GABAergic or glutamergic neurotransmission (Seagard et al, 2004). It was also observed that pharmacologically induced increases in blood pressure were accompanied by increases in endogenous anandamide in the nucleus tractus solitarius, pointing to a possible modulatory role.…”

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…Both AT 1 -and CB 1 -receptors were identified in the NTS, in the dorsal motor nucleus of vagus and in the paraventricular nuclei (Castelli et al, 2007;Partosoedarso et al, 2003;Seagard et al, 2004). On the basis of this findings it may be speculated that AT 1 receptorinduced activation of CB 1 receptors might take place in the dorsal vagal complex, however, whether there is an overlap in expression of CB 1 and AT 1 receptors in this brain area remains to be clarified.…”

Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB1 receptors

“…Inhibition of GABAergic and/or glutamatergic synaptic transmission by the cannabinoid agonists, however, has been documented in a number of other brain regions, including the hippocampus, cerebellum, and basal ganglia (12,24,25,49). Also, recordings in brain slices suggest that cannabinoid agonists can regulate the release of neurotransmitters such as glutamate and GABA through presynaptic receptor mechanisms in many regions of brain (45,46,53). Our data generally are consistent with these observations, although GABA rather than glutamate in the vlPAG appears to be preferentially regulated during EA.…”

“…ECs are produced in various regions of the brain in response to noxious stimuli and bind to cannabinoid type 1 (CB 1 ) receptors (14,55). Administration of exogenous cannabinoids into the nucleus tractus solitarii (NTS) facilitates baroreflex inhibition of renal sympathetic nerve activity, suggesting that ECs modulate cardiovascular reflex responses (46). Blockade of CB 1 receptors in the NTS of intact animals eliminates the facilitating effect that the EC anandamide has on baroreflex responses, indicating that ECs regulate cardiovascular reflexes through a GABAergic neurotransmission mechanism (46).…”

“…Administration of exogenous cannabinoids into the nucleus tractus solitarii (NTS) facilitates baroreflex inhibition of renal sympathetic nerve activity, suggesting that ECs modulate cardiovascular reflex responses (46). Blockade of CB 1 receptors in the NTS of intact animals eliminates the facilitating effect that the EC anandamide has on baroreflex responses, indicating that ECs regulate cardiovascular reflexes through a GABAergic neurotransmission mechanism (46). In an activity recording study in brain slices from the PAG (without detailing the PAG subdivision), investigators have documented that the EC system inhibits glutamatergic and GABAergic synaptic transmission through a CB 1 receptor mechanism (52,53).…”