Involvement of CB1 and TRPV1 receptors of the ventrolateral periaqueductal gray in physical stress-evoked cardiovascular responses during in rats

Abstract

The periaqueductal gray (PAG) is a mesencephalic structure that surrounds the cerebral aqueduct. The PAG was functionally divided into four longitudinal columns: the dorsomedial, dorsolateral, lateral and the ventrolateral (vlPAG). Microinjection of endocannabinoid or endovanilloid antagonists into the vlPAG blocked the cardiovascular responses to a physical stress: hemorrhage. Microinjection of excitatory amino acids into the vlPAG caused decreases in blood pressure, heart rate, sympathetic activity, as well as antinociception, quiescence and hyporeactivity. This syndrome is often associated with pathophysiological conditions such as the loss of large volumes of blood. Experimental studies have established that in mammals hemodynamic responses to blood loss consist of three phases: Phase I compensatory normotensive; Phase II decompensatory, hypotensive and phase III recompensatory post-hemorrhage, when the pressure returns to normal levels. Recent reports have shown that the endocannabinoid system is associated with the pathophysiology of hypotension in various forms of shock, including the hemorrhagic. Interestingly, it has been shown that the hypotension caused by blood loss was prevented by a systemic pretreatment with the CB1 antagonist SR141716; the CB1 receptors are densely expressed along the PAG. In the present study, we evaluated the participation of vlPAG CB1 receptors in the cardiovascular responses evoked by hemorrhage. Local microinjection of AM251 (0.25 nmol), a selective CB1 receptor antagonist, into the vlPAG caused a delayed onset of the hypotension, when compared to the control and the tachycardia evoked by hemorrhage was abolished. The pretreatment of the vlPAG with a lower dose of AM251 (0.025 nmol), abolished both the hypotension and the tachycardia caused by hemorrhage. Importantly, the pretreatment of the vlPAG with both doses of AM251, did not significantly alter the recompensatory phase of hemorrhage. We consider that the delayed hypotensive response observed after the pretreatment of vlPAG with the highest dose of AM251 (0.25 nmol), could be due to nonspecific effects of AM251. Much has been investigated on the interaction between the endocannabinoid system and the vanilloid system. Furthermore, recent findings indicate that TRPV1 receptors are also expressed in the PAG. Then, we pretreated the vlPAG with two doses of the transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine (2.5 and 15 nmol). Pretreatment of the vlPAG with 15 nmol of capsazepine significantly reduced the hypotension and tachycardia evoked by hemorrhage. However, when we microinjected capsazepine at a dose of 2.5 nmol, we observed total blockade of the hypotension and a reduction in the tachycardiac response evoked by hemorrhage. These data suggest that TRPV1 and CB1 receptors present in the vlPAG participate in cardiovascular modulation during hemorrhage.