anandamide and Urinary-Incontinence

The TRPV1 channel is mainly expressed in sensory nerves. Activation of the channel induces neuropeptide release from central and peripheral sensory nerve terminals, resulting in the sensation of pain, neurogenic inflammation, smooth muscle contraction and cough. The TRPV1 channel can be activated by vanilloids such as capsaicin, as well as endogenous stimulators including H(+), heat, lipoxygenase products and anandamide. TRPV1 channel function is upregulated by several endogenous mediators present in inflammatory conditions, which decreases the threshold for activation of the channel. Under these conditions, TRPV1 can be activated by physiological body temperature, slight acidification or lower concentration of TRPV1 agonists. There is evidence that TRPV1 plays a role in the development of pathophysiological changes and symptoms in several diseases. In this review, we discuss TRPV1 channel activation and regulation in normal and diseased conditions, the role of TRPV1 in pain, cough, asthma and urinary incontinence, and the potential use of TRPV1 antagonists as a novel therapy for these diseases.

Topics: Animals; Arachidonic Acids; Cough; Endocannabinoids; Hot Temperature; Humans; Hydrogen-Ion Concentration; Ion Channels; Lipoxygenase; Lung Diseases; Pain; Polyunsaturated Alkamides; TRPV Cation Channels; Urinary Incontinence

During the last few years, vanilloid substances and botulinum-A toxin were extensively investigated as new therapies for overactive bladder. Intravesical administration of capsaicin or resiniferatoxin--2 members of the vanilloid family--has been shown to increase bladder capacity and decrease urge incontinence in patients with neurogenic, as well as nonneurogenic, forms of detrusor overactivity. In addition, vanilloids have been shown also to reduce bladder pain in patients with hypersensitive disorders. Vanilloids are exogenous ligands of vanilloid receptor type 1 (VR1), an ion channel present in the membrane of type C primary afferent nerve fibers. This receptor, which plays a key role in pain perception and control of the micturition reflex, may be upregulated by nerve growth factor (NGF), a neurotrophic molecule detected in high concentrations in overactive detrusor tissue. Vanilloids, by reducing uptake of NGF through sensory neurons, may counteract VR1 upregulation. Intravesical injections of botulinum-A toxin, a neurotoxin produced by Clostridium botulinum, were shown to increase bladder capacity and to decrease urge incontinence episodes in patients with neurogenic detrusor overactivity. Botulinum-A toxin impedes the release of acetylcholine from cholinergic nerve endings at the neuromuscular junction, leading to paralysis of the detrusor smooth muscle.

Topics: Animals; Arachidonic Acids; Botulinum Toxins, Type A; Capsaicin; Diterpenes; Endocannabinoids; Humans; Nerve Growth Factor; Neurotoxins; Polyunsaturated Alkamides; Receptors, Drug; Urinary Bladder; Urinary Incontinence

Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin. We have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compound named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC(50) = 6 versus 0.7 nM), but more versatile in terms of structural modifications because of the presence of an additional functional group. Acetylation and phenylacetylation of rinvanil re-established and dramatically enhanced, respectively, its potency at hTRPV1. With a two-digit picomolar EC(50) (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC(50), 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, respectively, whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidation) of the double bond were tolerated. Finally, iodination of the aromatic hydroxyl caused a dramatic switch in functional activity, generating compounds that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compound was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.

Topics: Amidohydrolases; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Capsaicin; Carrier Proteins; Cell Line, Tumor; Endocannabinoids; Female; Ganglia, Spinal; Humans; In Vitro Techniques; Indicators and Reagents; Ion Channels; Neurons; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; TRPV Cation Channels; Urinary Bladder; Urinary Incontinence