Activating TRPV1 Channel By Application Of Capsaicin

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Describe the mechanisms in which activating TRPV1 channel by application of capsaicin

Pain is a sensory mechanism aimed at protecting an organism from damage. Chemical, thermal or mechanical stimuli stimulate unmyelinated c-fibres or thinly myelinated A nociceptive fibres, which induce action potentials that are conducted to the CNS and result in a protective response, whether withdrawal, egestion or an emotional response (Ueda 2006).  However, whilst pain is designed as a protective mechanism, there are times, such as with mechanical allodynia, when it is an unwanted response.  Therefore an understanding of how nocicptive fibres mediate the pain response is important in theorising methods by which pain can be effectively controlled.  As such the TRPV1 receptor that mediates the pain response to capsaicin is a useful target.

Capsaicin

Capsaicin is the active substance in chilli peppers and acts to cause apain response when it comes into contact with mucous membranes inmammals (Rang, Dale & Ritter 1999).

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It is known that the nociceptive response to capsaicin disappears aftera few applications (Rang, Dale & Ritter 1999) and repeated topicalapplication of capsaicin is able to increase the noxious heatthreshold, with the normal threshold returning within a short while oftreatment cessation (Nagy et al. 2004).  However, if applied to newbornanimals, capsaicin selectively destroys c-fibre afferents, leading toan inability to respond to painful or thermal stimuli (Rang, Dale &Ritter 1999). 

It is believed that the different responses to capsaicin are related to altered expression of the TRPV1 capsaicin receptor.

Pharmacology of the TRPV1 receptor

The 95kDa TRPV1 capsaicin receptor was first cloned in 1997 and is a 6transmembrane (TM) protein receptor, which shares similarity with otherreceptors in the TRP (transient receptor potential) family (Caterina etal. 1997).  TRPV1 derives its name due to it’s binding for vanilloidssuch as capsaicin; the critical binding region involving amino acids onTM2, 3 and 4, as illustrated in figure 1 below.
Figure 1. The membrane topology of the TRPV1 receptor, indicatingcrucial amino acid residues involved in receptor activation (Holzer2004)

When capsaicin or another ligand binds to the TRPV1 receptor, there isa rapid and large increase in calcium levels within seconds (Caterinaet al. 1997), leading to depolarisation in the nerve endings (Bartho etal. 2004).

There are no necessary second messengers required for the TRPV1receptor to be activated by capsaicin (Numazaki, Tominaga 2004). Thisis illustrated in the proposed model of figure 2, which shows a directconnection between ionic flux at the ion channel, cytosolicdepolarisation and the subsequent action potential.
Figure 2. The proposed model of TRPV1 function in a sensory neuron (Numazaki, Tominaga 2004)
 

TRPV1 in the sensitisation of c-fibres in the pain response

TRPV1 receptors are found on small to medium dorsal root ganglion (DRG)cells (Carlton, Coggeshall 2001) eg those that are unmyelinated andeither C or A fibres.  Given that these are the fibres known to beinvolved in nociception it is logical to conclude that TRPV1 receptorshave an important role in pain response.
TRPV1 activity is potentiated by heat (> 43C) and decreased pH. Currents evoked by heat application are very similar to those evokedvia nociception (Numazaki, Tominaga 2004) and inflammation causes anincrease in electrically activated neurons, correlated with an increasein TRPV1 expressing neurones (Amaya et al. 2003).

Normally 17% of unmyelinated c-fibres stain positively for TRPV1. However this proportion increases to 100% 48 hours after induction ofinflammation in the rat hindpaw (Carlton, Coggeshall 2001).  Localinflammation causes a 1.5 fold increase in TRPV1 expression (Amaya etal. 2003).  These results have been attributed to increased receptortransport, leading to increased receptor density. 
Nociceptive responses to bradykinin, substance P and histamine areabolished following capsaicin pre-treatment. Given the ability ofcapsaicin to destroy c-fibre afferents it was therefore concluded thatTRPV1 mediates nociception in c-fibres via these 3 inflammatorymediators (Ueda 2006).

TRPV1 in mechanical allodynia

Mechanical allodynia is chronic pain resulting from simple stimuli thatwould not normally be expected to cause pain.  It is believed to resultfrom a decreased threshold of nociceptive fibres and may arise fromabnormal inflammation caused by neuropeptides.  It has been shown thatthe same neuropeptides released in response to capsaicin administrationare also released following a constriction injury, mimicking mechanicalallodynia (Kanai et al. 2005).
Inflammatory mediators such as bradykinin may act to reduce the heatthreshold of the TRPV1, potentiating its activity (Nagy et al. 2004). However, currently, only in vitro, not in vivo data exist to supportthis hypothesis.  Alternatively endogenous ligands may be releasedduring inflammation and it is these that directly activate the TRPV1receptor.  The blockade of TRPV1 by capsaicin antagonists such ascapsazepine (Nagy et al. 2004) would appear to support the endogenousligand hypothesis.

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Recently the TRPV1 antagonist(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide(BCTC) was found to attenuate induced mechanical allodynia (Kanai etal. 2005).  The same study also indicated an increase in TRPV1 proteinlevels in the ipsilateral spinal cord, 7 to 14 days after a chronicconstriction injury that would be expected to cause pain.

TRPV1 mRNA is down-regulated in the somata of damaged sensory neuronesand sciatic nerve section causes a significant reduction in TRPV1levels (Hudson et al. 2001), believed to be due to the removal of nervegrowth factor and other target derived growth factors.  However thesame study showed that TRPV1 expression was found to increase inunmyelinated c-fibre afferents in undamaged neurones.  These resultsindicate that the pain experienced is due to responses from theundamaged fibres becoming more sensitised to TRPV1 activation.

Conclusion

It would appear that TRPV1 receptors may be involvedin the nociceptive response in mechanical allodynia via an upregulationof the receptors within intact neurons.  Therefore a potential avenuefor treatment would be the antagonism of TRPV1, which should relievesome of the experienced pain.  Capsaicin is able to act as ananalgesic, possibly due to an increase in the pain threshold, andfollowing an initial increase in pain.  However the exact role by whichcapsaicin is able to act as an analgesic in neuropathic pain are stillnot understood (Ueda 2006) so this needs to be fully elucidated beforeit is more widely used.

References

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Carlton, S.M. & Coggeshall, R.E. 2001, "Peripheral capsaicinreceptors increase in the inflamed rat hindpaw: a possible mechanismfor peripheral sensitization", Neuroscience letters, vol. 310, no. 1,pp. 53-56.
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