P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid ...

Molecular Physiology of P2X Receptors

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

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The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for nonreceptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

Pharmacokinetics and Pharmacodynamics of Cannabinoids

The term 'endocannabinoid' - originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands - now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.

The endocannabinoid system and its therapeutic exploitation

The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?

Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed.

Purinergic Signaling and Blood Vessels in Health and Disease

Cardiovascular effects of cannabinoids

There are nineteen different receptor proteins for adenosine, adenine and uridine nucleotides, and nucleotide sugars, belonging to three families of G protein-coupled adenosine and P2Y receptors, and ionotropic P2X receptors. The majority are functionally expressed in blood vessels, as purinergic receptors in perivascular nerves, smooth muscle and endothelial cells, and roles in regulation of vascular contractility, immune function and growth have been identified. The endogenous ligands for purine receptors, ATP, ADP, UTP, UDP and adenosine, can be released from different cell types within the vasculature, as well as from circulating blood cells, including erythrocytes and platelets. Many purine receptors can be activated by two or more of the endogenous ligands. Further complexity arises because of interconversion between ligands, notably adenosine formation from the metabolism of ATP, leading to complex integrated responses through activation of different subtypes of purine receptors. The enzymes responsible for this conversion, ectonucleotidases, are present on the surface of smooth muscle and endothelial cells, and may be coreleased with neurotransmitters from nerves. What selectivity there is for the actions of purines/pyrimidines comes from differential expression of their receptors within the vasculature. P2X1 receptors mediate the vasocontractile actions of ATP released as a neurotransmitter with noradrenaline (NA) from sympathetic perivascular nerves, and are located on the vascular smooth muscle adjacent to the nerve varicosities, the sites of neurotransmitter release. The relative contribution of ATP and NA as functional cotransmitters varies with species, type and size of blood vessel, neuronal firing pattern, the tone/pressure of the blood vessel, and in ageing and disease. ATP is also a neurotransmitter in non-adrenergic non-cholinergic perivascular nerves and mediates vasorelaxation via smooth muscle P2Y-like receptors. ATP and adenosine can act as neuromodulators, with the most robust evidence being for prejunctional inhibition of neurotransmission via A1 adenosine receptors, but also prejunctional excitation and inhibition of neurotransmission via P2X and P2Y receptors, respectively. P2Y2, P2Y4 and P2Y6 receptors expressed on the vascular smooth muscle are coupled to vasocontraction, and may have a role in pathophysiological conditions, when purines are released from damaged cells, or when there is damage to the protective barrier that is the endothelium. Adenosine is released during hypoxia to increase blood flow via vasodilator A2A and A2B receptors expressed on the endothelium and smooth muscle. ATP is released from endothelial cells during hypoxia and shear stress and can act at P2Y and P2X4 receptors expressed on the endothelium to increase local blood flow. Activation of endothelial purine receptors leads to the release of nitric oxide, hyperpolarising factors and prostacyclin, which inhibits platelet aggregation and thus ensures patent blood flow. Vascular purine receptors also regulate endothelial and smooth muscle growth, and inflammation, and thus are involved in the underlying processes of a number of cardiovascular diseases.

Vera Ralevic

Papers

Purinergic Signaling and Blood Vessels in Health and Disease

Cardiovascular effects of cannabinoids

Purinergic transmission in blood vessels.

Cannabinoid activation of recombinant and endogenous vanilloid receptors

Cannabinoid modulation of sensory neurotransmission via cannabinoid and vanilloid receptors: roles in regulation of cardiovascular function.