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 a pain response when it comes into contact with mucous membranes in mammals (Rang, Dale & Ritter 1999).

It is known that the nociceptive response to capsaicin disappears after a few applications (Rang, Dale & Ritter 1999) and repeated topical application of capsaicin is able to increase the noxious heat threshold, with the normal threshold returning within a short while of treatment cessation (Nagy et al. 2004).  However, if applied to newborn animals, capsaicin selectively destroys c-fibre afferents, leading to an 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 6 transmembrane (TM) protein receptor, which shares similarity with other receptors in the TRP (transient receptor potential) family (Caterina et al. 1997).  TRPV1 derives its name due to it’s binding for vanilloids such as capsaicin; the critical binding region involving amino acids on TM2, 3 and 4, as illustrated in figure 1 below.
Figure 1. The membrane topology of the TRPV1 receptor, indicating crucial amino acid residues involved in receptor activation (Holzer 2004)
 
When capsaicin or another ligand binds to the TRPV1 receptor, there is a rapid and large increase in calcium levels within seconds (Caterina et al. 1997), leading to depolarisation in the nerve endings (Bartho et al. 2004).

There are no necessary second messengers required for the TRPV1 receptor to be activated by capsaicin (Numazaki, Tominaga 2004). This is illustrated in the proposed model of figure 2, which shows a direct connection between ionic flux at the ion channel, cytosolic depolarisation 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 and either C or A fibres.  Given that these are the fibres known to be involved in nociception it is logical to conclude that TRPV1 receptors have 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 evoked via nociception (Numazaki, Tominaga 2004) and inflammation causes an increase in electrically activated neurons, correlated with an increase in 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 of inflammation in the rat hindpaw (Carlton, Coggeshall 2001).  Local inflammation causes a 1.5 fold increase in TRPV1 expression (Amaya et al. 2003).  These results have been attributed to increased receptor transport, leading to increased receptor density. 
Nociceptive responses to bradykinin, substance P and histamine are abolished following capsaicin pre-treatment. Given the ability of capsaicin to destroy c-fibre afferents it was therefore concluded that TRPV1 mediates nociception in c-fibres via these 3 inflammatory mediators (Ueda 2006).

TRPV1 in mechanical allodynia

Mechanical allodynia is chronic pain resulting from simple stimuli that would not normally be expected to cause pain.  It is believed to result from a decreased threshold of nociceptive fibres and may arise from abnormal inflammation caused by neuropeptides.  It has been shown that the same neuropeptides released in response to capsaicin administration are also released following a constriction injury, mimicking mechanical allodynia (Kanai et al. 2005).
Inflammatory mediators such as bradykinin may act to reduce the heat threshold of the TRPV1, potentiating its activity (Nagy et al. 2004).  However, currently, only in vitro, not in vivo data exist to support this hypothesis.  Alternatively endogenous ligands may be released during inflammation and it is these that directly activate the TRPV1 receptor.  The blockade of TRPV1 by capsaicin antagonists such as capsazepine (Nagy et al. 2004) would appear to support the endogenous ligand hypothesis.

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 et al. 2005).  The same study also indicated an increase in TRPV1 protein levels in the ipsilateral spinal cord, 7 to 14 days after a chronic constriction injury that would be expected to cause pain.

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

Conclusion

References

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