1. VANILLOID RECEPTORS
Aakrati Gupta
(2011H108048H)
16-04-2012

2. CONTENTS
 Introduction
 TRPV1 Structure
 TRPV1 Expression
 Implications in various disease states
 Agonists
 Antagonists

3. TRANSIENT RECEPTOR POTENTIAL
RECEPTORS(TRP)
TRP superfamily
TRPC TRPM TRPV TRPP TRPML TRPA TRPN
6 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

4. INTRODUCTION
TRP family
TRP channels were initially discovered in trp mutant strain of the fruit fly Drosophila.
 It includes > 30 cation channels, the majority of which are permeable for
divalent 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.

5. 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).

6. 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.

8. 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 neurons
o Non –neuronal cells:
 Keratinocytes, bladder urothelium, smooth muscle, liver,
polymorphonuclear granulocytes, pancreatic B cells, endothelial
cells, lymphocytes, macrophages
o Brain :
 Dopaminergic neurons of substantia nigra, hippocampal pyramidal
neurons, hypothalamus.

9. IN NEURONAL CELLS

10. 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

11. PARADOXICAL EFFECTS OF TRPV1
Nociception and pro-inflammatory effects
Diabetic Chronic
Faecal
painful persistent
incontinence
neuropathy cough
Oesophageal
Cancer pain osteoarthritis reflux
disease
Peripheral
Rheumatoid
neuropathic cystitis
arthritis
pain

14.  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.

15.  PERIPHERAL NEUROPATHIC PAIN
Study 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.

16.  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 mice
1. TRPV1 knockout mice,
2. wild-type control mice,
3. with the administration of a selective TRPV1 antagonist.
Int J Cancer 2004;109:182–8.

17.  Observations:
 TRPV1 knockout mice and TRPV1 antagonist-treated mice
demonstrated :
-ve ongoing and movement-evoked pain-related behaviour
-ve bone cancer severity
No 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.

18.  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.

19.  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

20.  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 cough
and 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

21.  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.

22.  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.

23.  Protective effects
Ischaemia and
reperfusion Hypertension
injury
Inflammatory
Sepsis
bowel disease
Obesity

24.  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–
reperfusion
injury was significantly impaired in TRPV1 knockout hearts.
European Journal of Pharmacology 627(2010) 1–7

25.  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.

26. 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).

27.  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 agonist
Model: rats , EPM of CB1 receptor
Observations:
ANANDAMIDE
CB1 TRPV1
Decrease in intracellular Ca2+ and attenuation of
Elevated
synaptic transmission calcium levels and potentiated synaptic transmission

28.  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

29.  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.

31.  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.

32. 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

33.  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 .

34.  Conclusions :
 blockade of TRPV1 receptors unmasks the anti-dyskinetic effects of
FAAH inhibitors.
 CB1 and TRPV1 receptors play opposite roles in levodopa-induced
dyskinesias.

35. 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. Untreated
2. Vehicle
3. 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.

36.  (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.

37.  Physiological functions
thermoregulation
neurogenesis
Urinary bladder
function

38. AGONISTS

39. ANTAGONISTS

40. 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