ABSTRACT
The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation.
Subject(s)
Transient Receptor Potential Channels/physiology , Animals , Brain/physiology , Cardiovascular Physiological Phenomena , Humans , Inflammation/physiopathology , Neurons/physiology , Obesity/physiopathologyABSTRACT
Substance P is a neuropeptide that is released from sensory nerves and which has a number of pro-inflammatory effects. In this article, we review the evidence for a role of substance P in arthritis, both in experimental animal models and rheumatoid arthritis patients. Substance P expression is altered in the joint and dorsal horn of arthritic animals, exogenous substance P and neurokinin 1 (NK(1)) receptor antagonists modulate responses in the joint, and there is some evidence for a role of substance P in human joint disease. However, the therapeutic potential of NK(1) receptor antagonists in the treatment of rheumatoid arthritis remains controversial.
Subject(s)
Arthralgia/metabolism , Arthritis/metabolism , Joints/innervation , Sensory Receptor Cells/metabolism , Substance P/metabolism , Animals , Arthralgia/drug therapy , Arthralgia/physiopathology , Arthritis/drug therapy , Arthritis/physiopathology , Humans , Joints/physiopathology , Neurokinin-1 Receptor Antagonists , Posterior Horn Cells/cytology , Posterior Horn Cells/metabolism , Receptors, Neurokinin-1/metabolism , Sensory Receptor Cells/cytology , Substance P/pharmacology , Synovial Membrane/innervation , Synovial Membrane/physiopathologyABSTRACT
This review examines the biological significance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the profile of pharmacological activity of the parent, non-steroidal anti-inflammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-inflammatory and anti-nociceptive efficacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic benefit in a wide variety of disease states including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Arteriosclerosis/drug therapy , Arteriosclerosis/metabolism , Coronary Restenosis/drug therapy , Digestive System/drug effects , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Nitric Oxide/metabolism , Nitric Oxide Donors/adverse effects , Osteoporosis/drug therapy , Osteoporosis/metabolism , Pain/drug therapy , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic useABSTRACT
Initial experiments in the present study investigated the effects of epidermal growth factor (EGF), interleukin 1beta (IL-1beta) and sodium nitroprusside (a nitric oxide donor) on the output of prostaglandins from guinea-pig uterus on day 7 of the oestrous cycle. Superfusion of day 7 guinea-pig uterus in vitro with either EGF or sodium nitroprusside increased the output of PGF(2alpha) and 6-keto-PGF(1alpha), but not of PGE(2). IL-1beta had no effect on the output of these three prostaglandins. EGF still increased the output of PGF(2alpha), but did not increase the output of 6-keto-PGF(1alpha) in a calcium-depleted superfusate. Subsequent experiments investigated the effect of sodium nitroprusside on contractile activity of day 7 guinea-pig uterus. Basal spontaneous activity of both the intact uterus and isolated myometrium superfused in vitro was low. Sodium nitroprusside increased the contractile activity of these tissues two- to fourfold. EGF did not affect the contractile activity of the uterus, indicating that sodium nitroprusside-induced contractions are not due to increased prostaglandin production. Overall, the findings indicate that EGF and nitric oxide may act as mediators in the mechanism by which oestradiol acting on a progesterone-primed uterus stimulates the increase in PGF(2alpha) production by the guinea-pig uterus necessary for luteolysis. Nitric oxide may increase the spontaneous activity of the uterus when this activity is low.
