Neuropeptides
-
The aim of the present work was to investigate the role of brain μ, κ and δ opioid receptors in the central serotonergic mechanisms regulating blood pressure in rats. The data obtained show that: (1) pharmacological activation of central 5-HT(3) receptors yields a significant decrease in blood pressure; (2) the blockade of those receptors by a selective antagonist induces an acute hypertensive response; (3) the pharmacological blockade of central opioid receptors by three different opioid antagonists exhibiting variable degrees of selectivity to μ, κ and δ opioid receptors always suppressed the hypotensive response induced by central 5-HT(3) receptor stimulation; (4) the blockade of opioid receptors by the same opioid antagonists that impaired the hypotensive effect of central 5-HT(3) receptor stimulation failed to modify blood pressure in animals not submitted to pharmacological manipulations of central 5-HT(3) receptor function. It is shown that a 5-HT(3) receptor-dependent mechanism seems to be part of the brain serotonergic system that contributes to cardiovascular regulation since the hypertensive response observed after ondansetron administration indicates that central 5-HT(3) receptors exert a tonic inhibitory drive on blood pressure. Furthermore, the data obtained here clearly indicate that the hypotensive response observed after pharmacological stimulation of central 5-HT(3) receptors depends on the functional integrity of brain μ, κ and δ opioid receptors, suggesting that a functional interaction between serotonergic and opiatergic pathways in the brain is part of the complex, multifactorial system that regulates blood pressure in the central nervous system.
-
Cannabinoid-induced antinociception relies on activation of inhibitory cannabinoid receptors (CB1) in the peripheral and central nervous system. However, most cannabinoids at higher concentration also activate excitatory ionotropic transient receptor potential (TRP) channels coexpressed with CB1 in primary nociceptive neurons that contain and release calcitonin gene-related peptide (CGRP) upon activation. Over a wide concentration range (0.01-100μM) we investigated the molecular action principles of the endocannabinoid anandamide and of the plant-derived Δ(9)-THC that can be prescribed for analgesia. ⋯ CGRP release induced by unspecific depolarization (KCl) was not modulated by cannabinoids. An incidental finding was that global CB1(-/-) showed reduced heat sensitivity, almost as low as TRPV1(-/-) and in accord with their behavioral phenotype. In conclusion, the antinociceptive potency of peripherally acting CB1 agonists is not restrained by opposing irritant effects through TRPV1 but by their own limited efficacy and narrow concentration-response relationship.