Although ultrastructural alterations in sensory neurons could accompany the functional desensitization induced by capsaicin, it has been suggested that at low desensitizing doses the impaired function is due to a dynamic, time dependent decrement of sensory responsiveness (Szolcsanyi et al., 1975; Szolcsanyi, 1990, 1993) and not due to the acute cell death as induced by a neurotoxin (Jancso and Kiraly, 1981; Jancso et al., 1985, 1987). The mechanism of long-lasting mitochondrial alterations evoked by systemic capsaicin pretreatment, both in neonatal and adult rats, is an interesting issue for further research, as is the finding that in the neonatal rat the cell death develops after a week owing to the inhibited NGF uptake through the impaired nerve terminals (Szolcsanyi et al., 1998b).
In vivo single unit recordings from C-polymodal nociceptors revealed that the number of action potentials evoked by noxious heat, capsaicin, bradykinin or mechanical stimuli were decreased or abolished after the close arterial injection of capsaicin to the rabbit ear over a ninefold dose range, although each sensor still responded to at least one type of stimulation (Szolcsanyi, 1987a). The threshold elevation to capsaicin or mechanical stimuli was also observed in the rat a few days after systemic capsaicin treatment (Szolcsanyi et al., 1988).
Details about the mechanism of acute capsaicin desensitization were discovered in studies of membrane currents of cultured dorsal roor ganglion neurons (Bevan and Szolcsanyi, 1990; Bevan and Docherty, 1993; Vlachova and Vyklicky, 1993; Piper et al., 1999; Szallasi and Blumberg, 1999)- It seems that phosphorylation of the capsaicin receptor/ion channel is necessary for a maintained capsaicin sensitivity (Koplas et al., 1997; Piper et al., 1999)- Calcium entry through the activated ion channel, but not from internal stores, may promote dephosphorylation of the VR1 receptor and in this state the channel shows outward rectification which is linked to desensitization (Piper et al., 1999)- The calcium-induced dephosphorylation of the capsaicin VR1 receptor is probably mediated by the activation of caicineurin (Docherty et al., 1996). As Figure 16.5 shows that the desensitized state of the VR1 receptor might result in a pronounced inhibition of the activation of the sensory nerve endings by bradykinin or lipoxygenase products.
Beyond the desensitization of the capsaicin VR1 receptor, the other scope is the functional desensitization of the sensory nerve terminal to stimuli which do not activate the VR1 receptors. One of these mechanisms is the lasting inhibition of voltage-gated calcium channels due to the markedly enhanced intracellular calcium ion concentration which takes place after VR1 activation by capsaicin or resiniferatoxin (Bevan and Szolcsanyi, 1990; Bevan and Docherty, 1993). The second indirect mechanism is the inhibition of voltage-gated Na+ channels by capsaicin. Capsaicin in a low concentration range (KV2 ~ 0.45 JxM) inhibits the action potential generation only in the capsaicin-sensitive subpopulation of neurons (Liu et al., 2001, unpublished observations). The third putative mechanism for sensory desensitization is related to the mitochondrial impairment which is unusually iong-iasting after systemic treatment similar to the functional desensitization (Szolcsanyi et al., 1975; Szolcsanyi, 1993). Recently, it has been shown that after acute exposure of capsaicin to cultured dorsal root ganglion neurons, mitochondrial depolarization develops (EC50: 6.9 (xM) which might induce the mitochondrial swelling in vivo (Dedov et al., 2001). The role of these putative mechanisms in the capsaicin-induced sensory desensitization needs further research. In this context it is worth noting that most of these results were obtained from dorsal root ganglion neurons which were cultured in a NGF supplemented medium. Acute NGF application enhances the inward current induced by capsaicin and counteracts the development of desensitization (Shu and Mendel, 1999). Therefore, for technical reasons, the role of ion channels and mitochondria in capsaicin-induced sensory desensitization has not been tested on sensory nerve terminals under natural environmental conditions.
From the point of view of drug development, a slow channel opener VR1 agonist, which could produce desensitization without spike generation at the nociceptors might be a rational approach. Several new compounds were synthesized 25 years ago (Szolcsanyi and Jancso Gabor, 1975) to achieve this goal and recently a novel non-pungent capsaicin analogue with a clear therapeutic window has been introduced (Urban et al., 2000).
Was this article helpful?