polymodal : responding to several different forms of sensory stimulation
Solid arrows indicate transient receptor potential vanilloid subfamily, member 1 (TRPV1)-sensitizing stimuli. The red arrows indicate negative regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), calcium and calmodulin. Receptors and cognate ligands known to mediate the sensitization of TRPV1 are shown on the left. These largely sensitize TRPV1 through protein-kinase activation, although increased arachidonic acid metabolite production and PIP2 hydrolysis are also important. Coloured circles represent amino-acid residues that have been identified to be important in particular functions: orange, vanilloid binding (Y511, S512, L547, T550); blue, protein kinase phosphorylation sites (S116, T370, S502, T704, S800); and green, low-pH activation (E600, E646). The red line indicates the carboxy-terminal domain of TRPV1, which has been shown to interact with both PIP2 and calmodulin
Diabetic patients oftendemonstrate one or more types of stimulus-evoked pain includingincreased responsiveness to noxious stimuli (hyperalgesia), inaddition to hyper-responsiveness to normally innocuous stimuli(allodynia).
no TRPV1 agonists so far are available inclinic to treat cardiovascular and gastrointestinal diseases..The majordrawbacks of currently available agonists for TRPV1 include lowselectivity (such as the endogenous ligands), low bioavailability (suchas rutaecarpine) or high toxicity (such as capsaicin
Neuroscience 204 (2012) 186–192CANNABINOID TYPE 1 RECEPTORS AND TRANSIENT RECEPTORPOTENTIAL VANILLOID TYPE 1 CHANNELS IN FEAR AND ANXIETY—
Exp Neurol. 2007 November ; 208(1): 110–119.Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to breakdown anandamide(cb1 agonist6-hydroxydopamine (6-OHDA) hydrochloride
Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to breakdown anandamide(cb1 agonist6-hydroxydopamine (6-OHDA) hydrochlorideCatalepsy is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain.
Catalepsy (from gr. κατάληψις "catch") is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain.
Pharmacol Res. 2010 Jun;61(6):531-6. Epub 2010 Feb 10.
Current clinical status of TRPV1-targeted therapiesNature Reviews Drug Discovery 6, 357-372 (May 2007)
CONTENTS Introduction TRPV1 Structure TRPV1 Expression Implications in various disease states Agonists Antagonists
TRANSIENT RECEPTOR POTENTIAL RECEPTORS(TRP) TRP superfamily TRPC TRPM TRPV TRPP TRPML TRPA TRPN6 types(mammals 2 types(non- Activated by mammals) vanilloids(capsaicin) TRPV1 Heat activated receptors & non Osm-9 TRPV2 In drosophila selective for cations(also Ca2+) TRPV3 Nanchung TRPV4 TRPV5 High Ca2+ selectivity & low temperature TRPV6 sensitivity
INTRODUCTIONTRP familyTRP channels were initially discovered in trp mutant strain of the fruit fly Drosophila. It includes > 30 cation channels, the majority of which are permeable fordivalent and monovalent cations, including Ca2+, Na+, and Mg2+. They have broad tissue distribution and may participate in divergent functions such as: visual and auditory functions, speech, pain signal transduction, regulation of blood circulation, gut motility, mineral absorption and fluid balance, airway and bladder hypersensitivities, cell survival, growth and death.
TRPV1 It is a non-selective cation channel. in humans, is encoded by the TRPV1 gene It has been considered as a ‘pathological’ receptor, it has a significant role in the pain transduction pathway and pro- inflammatory role in a variety of disease and injury states. It is activated by capsaicin, the main pungent principle of hot chilli peppers. It is a polymodal TRP channel that can be activated by noxious heat, pH changes, fatty acid amides, and endogenous lipid ligands. First cloned from rat dorsal root ganglia(DRG).
STRUCTURE OF TRPV1 It is a single polypeptide, 838 amino acid, 95kD. It has a large intracellular amino-(N-) and carboxy-(C-) terminal and 6 transmembrane segment. An additional short hydrophobic stretch between TM5 and TM6. TRPV-1 subunits assemble as tetramers. N- terminus (432 a.a) has 3 ankyrin repeats(essential for channel function). C- terminus(154 a.a) has a TRP domain which serves as a molecular determinant. C- terminus has amino acid residues for PIP2 binding To the N-terminus PKA and PKC binds.
TRPV1 EXPRESSION Neuronal cells: small to medium diameter primary afferent fibres. A-δ myelinated fibres sensory neurons unmyelinated C fibres Dorsal root ganglia(DRG) Trigeminal neuronso Non –neuronal cells: Keratinocytes, bladder urothelium, smooth muscle, liver, polymorphonuclear granulocytes, pancreatic B cells, endothelial cells, lymphocytes, macrophageso Brain : Dopaminergic neurons of substantia nigra, hippocampal pyramidal neurons, hypothalamus.
IN NON NEURONAL CELLS Location/Cell type Function Keratinocytes Release of pro-inflammatory mediator, sensor for noxious cutaneous stimulation Bladder urothelial cells Regulation of bladder reflex contractions Smooth muscle Vasoconstriction Cerebromicrovascular Contribution to the regulation endothelial cells of cerebral blood flow and BBB permeability polymorphonuclear Possible pro-inflammatory granulocytes, role, yet the role of TRPV1 on Lymphocytes, macrophages cells of the immune system is currently elusive Preadipocytes and adipose Regulation of adipogensis tissue
PARADOXICAL EFFECTS OF TRPV1Nociception and pro-inflammatory effects Diabetic Chronic Faecal painful persistent incontinence neuropathy cough Oesophageal Cancer pain osteoarthritis reflux disease Peripheral Rheumatoid neuropathic cystitis arthritis pain
DIABETIC NEUROPATHY:Study done in: STZ induced diabetic rats.Observations: TRPV1 protein levels were down-regulated, while the function of TRPV1 was increased in the DRG neurones isolated from early diabetic rats. Also DRG neurons from diabetic rats exhibit increased levels of oxidative stress in vitro, an effect that is reduced by incubation of cells with the TRPV1 antagonist, capsazepine.Conclusion: early diabetic neuropathy is associated with enhanced function of TRPV1 in DRG neurones , which may result in compensatory down- regulation of TRPV1 receptor expression.
PERIPHERAL NEUROPATHIC PAINStudy done: total or partial sciatic nerve transection, or spinal nerve ligation.Observations: TRPV1 mRNA levels were downregulated in the somata of damaged sensory neurones. TRPV1-immunoreactivity was significantly reduced in the somata of damaged DRG neuronal profiles, compared to controls. In case of partial transection or spinal nerve ligation, TRPV1 expression was increased in the undamaged DRG somata compared to controls.Conclusion: The persistence of TRPV1 expression in sites close to nerve injury,although down-regulated in injured nerves, is possibly due to depletion of growth factors such as NGF in injured nerves.
CANCER PAIN chronic bone pain(due to bone cancer)or metastases of non-bone primary tumours as breast, prostate and lung. osteoclast-induced bone remodelling is accompanied by the robust production of extracellular protons, which are known to be potent activators of primary afferent neurones. acidic microenvironment produced by osteoclasts contributes to bone cancer-associated pain via activation of acid-sensitive nociceptors which innervate the marrow and mineralised bone. Study done in : osteolytic sarcoma cell-induced-bone cancer model of mice1. TRPV1 knockout mice,2. wild-type control mice,3. with the administration of a selective TRPV1 antagonist. Int J Cancer 2004;109:182–8.
Observations: TRPV1 knockout mice and TRPV1 antagonist-treated mice demonstrated :-ve ongoing and movement-evoked pain-related behaviour-ve bone cancer severityNo effect on tumour growth Conclusions: 3 mechanisms contribute simultaneously to activation and sensitisation of TRPV1 receptors expressed by sensory fibres innervating the tumour-bearing joint . inflammation, tumour-released products and tumour-induced injury to primary afferent neurones.
ACUTE AND CHRONIC ARTHRITIS: neuropeptide-containing nerve fibres are present in the knee joint synovium and adjacent bone. levels of neuropeptides are significantly increased in samples of synovial fluid from patients with rheumatoid arthritis. 1.Study done : CFA-induced hind paw inflammation Observation: Myelinated axons were not affected during inflammation. Conclusion: an increase in the number of unmyelinated sensory axons expressing TRPV1 is one of the mechanisms underlying peripheral sensitisation in inflammation.
2. Study done : wild-type mice and TRPV1 knockout mice after intra-articular injection of CFA.Observation: knee swelling and vascular hyperpermeability were significantly higher in the CFA-treated joints of wild-type mice in comparison to TRPV1 null mice. No effect on leukocyte accumulation and cytokine production. thermal hyperalgesia and joint swelling were decreased in TRPV1 knockout mice compared with wild-type controls after intraarticular injection of mouse recombinant (TNF-α)Conclusion: (TNF-α) requires the presence of TRPV1 receptors to function
AIRWAY HYPERSENSITIVITY: number of neuropeptide CGRP containing nerves in the airway submucosa of patients with chronic persistent cough was shown to be increased. Also as the cough reflex is mediated by the activation of A-δ fibres, in addition to C-fibres.(TPRV1 present in these) Study done in: capsaicin-induced cough in guinea-pigs Observations: TRPV1 antagonist, capsazepine, inhibited the capsaicin-induced coughand the endogenous TRPV1 ligand, anandamide, induced coughing. Conclusion: The activation of A-δ fibres and C-fibres in the airways of guinea-pigs induced by decreasing pH involves TRPV1 as protons increase the TRPV1 channel function .An increase in the content of protons in exhaled breath condensate in chronic cough
FAECAL INCONTINENCE: Faecal urgency is a distressing, debilitating disorder in rectal cancer and IBD. Rectal sensation is conveyed by the polymodal C-fibres and A-δ fibres. in patients suffering from rectal hypersensitivity, the number of TRPV1-expressing nerve fibres was increased in muscle, submucosal and mucosal layers of rectal biopsy samples.
OESOPHAGEAL REFLUX DISEASE some patients perceive oesophageal acid exposure as painful, suggesting that visceral hyperalgesia may contribute to their symptoms. Study: capsaicin injection into the oesophageal wall resulted in severe chest pain and heartburn. Observations: TRPV1 immunoreactive fibres were increased in patients with erosive oesophagitis. increased acid exposure is associated with an increase in the density of nerve fibres expressing TRPV1.
TRPV1 in CVS and GIT: TRPV1 rich nerves are densely distributed in the CV and GI system. activation of TRPV1 either by endogenous ligands or by exogenous agonists exert hypotensive /protective effects against these systems injury through stimulating the synthesis and release of NT such as CGRP and substance P.1.CVS: Study done in: isolated rat heart Observations: cardioprotection provided by CGRP- or capsaicin-induced preconditioning was abolished by CGRP-(8–37), the selective CGRP receptor antagonist. Also preconditioning-induced cardiac protection against ischemia– reperfusioninjury was significantly impaired in TRPV1 knockout hearts.European Journal of Pharmacology 627(2010) 1–7
Conclusion: Activation of TRPV1 either by endogenous or exogenous ligand exert beneficial effects against cardiac injury. TRPV1 gene deletion results in excessive inflammation, disproportional left ventricular remodeling, and deteriorated cardiac function after myocardial ischemia, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodelling.2.GIT: It is rich in TRPV1 nerves, play pivotal role in the maintenance of gastrointestinal mucosa integrity against injurious interventions. also found in non-nervous tissue such as gastric epithelial cells, gastrin cells etc.
NO DRUG Study done in: TRPV1 knockout mice, isolated human antral glands.o Observations: luminal acidification did not activate mechanosensory neurons in TRPV1 knockout mice. activation of TRPV1 by capsaicin was able to stimulate the secretion of gastrin from antral glands. Conclusion: TRPV1 exerts multiple physiological functions as acid secretion , intestinal motility and visceral sensation to gastrin secretion. Mechanism of protection: release of NT (CGRP ) and the activation of cyclooxygenase-1 enzymes(inducing the production of prostaglandin E2).
IN ANXIETY: TRPV1 is expressed also in the brain, where it seems to be Neuroscience 204 (2012) 186–192 involved in antinociception, locomotor control, and regulation of affective behavior. Endogenous agonistModel: rats , EPM of CB1 receptorObservations: ANANDAMIDE CB1 TRPV1 Decrease in intracellular Ca2+ and attenuation of Elevated synaptic transmission calcium levels and potentiated synaptic transmission
This suggests a tripartite regulatory system with antagonistic effects of CB1 and TRPV1, which are tied together by the same endogenous ligand. Such a system may have important implication for the modulation of behavioural responses
TRPV1 is also present in glutamatergic synapses, but its role in fear and anxiety is less well explored than that of CB1.Study : systemic injection of the TRPV1 antagonist capsazepine in rats in the EPM test reduced anxiety-like behavior. Also behavioral analyses of TRPV1 knockout mice(i.e.decreased anxiety in the EPM , impaired fear expression in response to a tone) strengthened this notion that TRPV1 affects anxiety diametrically opposite to CB1.
Conclusion: Opposite roles of CB1 receptors and TRPV1 channels in synaptic transmission, fear, and anxiety: whereas activation of CB1 receptors promotes acute fear adaptation and decreases anxiety, TRPV1 channels exert anxiogenic actions.
TRPV1 AND PARKINSON’S DISORDER Problem with L-dopa : dyskinesias and psychiatric complications. Endocannabinoid/endovanilloid system - an important modulator of basal ganglia functions and its pharmacologic manipulation can be a therapy to alleviate L-dopa induced dyskinesias. Study done in: Male Wistar rats DA-denervating lesions were performed by unilateral injection of 6- OHDA. Two weeks after the lesion, the rats were screened for apomorphine- induced contralateral rotation to assess the efficacy of the lesion. Net contralateral turns were calculated by number of ipsilateral - contralateral rotations. Only rats displaying more than 300 rotations per 30 min (corresponding to about 90% depletion of tyrosine hydroxylase (TH) positive neurons were included in the study.Exp Neurol. 2007 November ; 208(1): 110–119
daily injection of levodopa + carbidopa for up to 12 days, led to a gradual development of increasingly severe axial, limb, locomotor and oro-facial abnormal involuntary movements (AIMs). Observations:(Catalepsy and AIM score) Administration of the CB1 agonist WIN 55, attenuated levodopa- induced axial, limb and oral AIMs dose-dependently via a CB1– mediated mechanism, it had no effect on locomotive AIMs. URB597, a potent FAAH inhibitor alone , did not affect AIMs scoring despite its ability to increase anandamide concentration throughout the basal ganglia. As known that anandamide can also bind and activate TRPV1 receptors. URB597+ TRPV1 antagonist capsazepine- significantly decreased all AIMs subtypes .
Conclusions : blockade of TRPV1 receptors unmasks the anti-dyskinetic effects of FAAH inhibitors. CB1 and TRPV1 receptors play opposite roles in levodopa-induced dyskinesias.
TRPV1 AND ALZIEMER’S DISEASE To investigate both the basal and beta-amyloid peptide impaired cognitive performance of D3R((-/-)) mice, and the role therein of endocannabinoids/endovanilloids. Pharmacol Res. 2010 Jun;61(6):531-6 Study done in : D3R knock out mice D3R((-/-)) and wild type(WT) mice were divided into 3 groups:1. Untreated2. Vehicle3. beta-amyloid peptide 1-42(BAP). (TRPV1) antagonist SB366791, were injected intraperitoneally for 11 /7 days. The retention test was performed 1, 7 and 14 days after the learning trial. Observations: D3R((-/-)) mice exhibited a better basal cognitive performance as compared to WT mice , which was reversed by TRPV1 antagonism.
(TRPV1) antagonist SB366791 did not affect the cognitive performance of healthy mice, but fully counteracted BAP 1-42- induced amnesic effects in both D3R((-/-)) and WT mice -when administered for 11 days when administered for 7 days, only transiently affected WT mice and caused more prolonged cognitive ameliorations in D3R((-/-)) mice. Conclusion : there is involvement of D3R and TRPV1 in cognitive processes and the A beta peptides inhibit memory retention in mice through the involvement of endovanilloids.
Physiological functions thermoregulation neurogenesis Urinary bladder function
EXPRESSION IN RETINA TRPV1 was detected in astrocytes, blood vessels, microglial cells and in neurons, indicating that this receptor could be involved in both visual coding and generating signals to provide retinal homeostasis.Int. J. Devl Neuroscience 27 (2009) 709–718