Immunocytochemical localization of capsaicin VR1TRPV1 receptors

Immunoreactivity to the rVRl receptor (Caterina et al., 1997; Tominaga et al., 1998; Guo et al., 1999; Mezey et al., 2000) and its mRNA (Helliwell et al., 1998; Michael and Priestley, 1999;

Mezey et al., 2000) were in accord with the data of binding studies with (3H]RTX (Winter et al., 1993; Szallasi and Blumberg, 1999), and revealed important new localizations as well.

Localization in sensory neurons

Immunoreactivity of rVRl or the in situ hybridization of its mRNA was detected in the B-type small or medium sized neurons in colocalization with TrkA or IB4 lectin markers in dorsal root ganglia and also in trigeminal, nodosal and jugular ganglia. No hybridization signal was observed in sympathetic ganglia (Helliwell et al., 1998). A high proportion of colocalization of VR1 immunoreactivity was observed with substance P, CGRP, P2X3 purinoceptor (Guo et al., 1999) and in IB4 positive population with somatostatin (Michael and Priestley, 1999).

In peripheral nerves and neural plexuses, as well as in the central terminals of primary afferent neurons in the superficial dorsal horn, VR1 positive fibers were also described (Tominaga et al., 1998; Guo et al., 1999). VR1 immunoreactivity was associated with the plasma membrane of unmyelinated fibers having clear vesicles, as well with axonal microtubules and Golgi complex (Tominaga et al., 1998; Guo et al., 1999).

Localization in the brain

Although (3H]RTX autoradiography failed to detect high affinity specific binding in different brain regions (Szallasi et al., 1995) and in situ hybridization of mRNA encoding VR1 did not indicate positivity in the brain, a recent elegant and more sensitive approach with reverse transcription-PCR was successful in this line (Mezey et al., 2000). Whether these differences indicate a much lower level of VR1 expression in the brain than in the sensory neurons needs further research.

VRl-immunoreactivity and mRNA for VR1 positive neurons in rat and human brain were scattered in different regions, including the preoptic area of the hypothalamus. The strongest VR1 mRNA signals were detected in the following areas: all cortical areas, septum, hippocampus dentate gyrus, substantia nigra (zona compacta), cerebellum, locus coeruleus and inferior olive. In rat hypothalamus VR1 mRNA-expressing neurons and capsaicin-induced glutamate release have been reported (Sasamura et al., 1998). It was striking that in rats treated with capsaicin in the neonatal age, although VR1 mRNA in DRG and nucleus of the spinal trigeminal nerve was diminished, its expression in other areas of the brain did not differ from that of the controls (Mezey et al., 2000).

The functional significance of the VRl-encoding neurons in the central nervous system is a challenging new field for further research. Capsaicin-sensitive neurons in the medial preoptic area serve as warmth sensors in thermoregulatory heat loss responses, as postulated a long time ago (Jancso-Gabor et al., 1970; Szolcsanyi et al., 1971) and repeatedly confirmed by other groups (Szolcsanyi, 1982, 1983; Hori, 1984; Pierau et al., 1986). In rats after adult pretreatment with capsaicin or resiniferatoxin a similar long-lasting mitochondrial swelling was observed in the preoptic area as that in the small neurons of the dorsal root ganglia (Joo et al., 1969; Szolcsanyi etal., 1971, 1975, 1990; Szallasi etal., 1989). Therefore a lower level of VR1 mRNA expression after adult pretreated rats, combined with an ultrastructural search for the characteristic cellular changes induced by capsaicin and resiniferatoxin in sensory neurons might be a possible good starting point for a morphological approach. Regarding their functional role, it should be remembered that noxious heat is not an adequate stimulus for VR1 except for the exteroceptors, while the chemical excitability feature of these neural elements might serve chemosensor functions in regulations of the internal environment.

It is worth noting that a few examples of VR1 expression have been shown also in non-neural tissues and the first data for H3RTX binding, Ca++ uptake and desensitization to the effects of capsaicin and resiniferatoxin described in Cg rat glioma cells and mast cells were in a remarkably similar concentration range as that of the DRG cells (Biro et al., 1998).

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