The heat is on: does direct application of capsaicin to autonomic nerves produce a specific deafferentation?

The discovery that capsaicin could excite and block transmission in small-diameter afferent nerve fibres provided an important tool for many researchers to investigate the role of this class of neuron in the regulation of physiological and pathophysiological processes. Systemic administration of capsaicin to neonatal animals produces a life-long deafferentation of all capsaicin-sensitive neurons and, in adults, produces a temporary ‘defunctionalization’ (Holzer, 1991). However, for those interested in reflex regulation of gastrointestinal (GI) function, these useful techniques were limited because the gut receives a dual afferent innervation from both the craniosacral and the thoracolumbar outflow from the central nervous system. The use of perineural application of capsaicin to nerve bundles provided an extremely important tool to determine the specific role of an afferent pathway in homeostatic reflexes. For example, total cervical or subdiaphragmatic vagal transection had been used experimentally to demonstrate a vago-vagal reflex pathway in the regulation of gastric motility and secretion, but delineation of the vagal afferent pathway was confounded by concomitant removal of the vagal efferent pathway. Application of capsaicin to the cervical vagal trunks clearly showed a role for the vagal afferent pathway in mediating inhibition of gastric emptying in response to gut peptides and intestinal nutrients (Raybould & Tache, 1988; Raybould & Holzer, 1992). Taken together with morphological studies (in particular those of Powley and his group; see Powley & Philips, 2002) and electrophysiological recordings (for example, Blackshaw & Grundy, 1990), the importance of vagal afferent neurons in the regulation of postprandial gastrointestinal function became evident. Observations using perineural application of capsaicin were also key in uncovering the ability of the gut peptide cholecystokinin to act via the vagal afferent pathway to inhibit food intake (South & Ritter, 1988). Fast forwarding to today, these initial observations led to profound changes in the way we think about the role of the gut and the gut–brain axis in control of body weight and glucose homeostasis. Decades later, however, it is not necessarily surprising to find that direct application of capsaicin to nerve bundles does not produce a specific ‘defunctionalization’ of afferent neurons, as previously supposed (or hoped). In this issue of The Journal of Physiology, Browning et al. (2013) convincingly show that perivagal application of capsaicin induces a degeneration of vagal efferent neurons and a decrease in vagal efferent responses. Researchers using perineural application of capsaicin attempted to control for the specificity of the treatment, but Browning et al. (2013) perform a number of well-designed morphological and electrophysiological experiments that clearly show the lesion produced by perivagal application of capsaicin is not restricted to vagal afferent fibres. One can quibble with the technique of capsaicin application – the use of DMSO and ethanol as the vehicle rather than oil as used by most previous investigators – oil allows for a much more controlled, local application with reduced risk of systemic absorption. The important message from the data in this study is to call into question some previous conclusions that the vagal afferent pathway is the sole mediator of changes in GI function in response to peripheral stimuli. The receptor for capsaicin has been identified and mapped, and capsaicin (particularly at high concentrations) has been shown to have non-TRPV1 receptor-mediated effects. Earlier publications showing altered functional response to vagal ‘efferent’ stimulation by perineural application of capsaicin ascribed these unexpected effects to retrograde activation of vagal afferent neurons or the lack of input to second-order neurons in the nucleus tractus solitarii as being important in the function of the overall reflex pathway (Raybould et al. 1990; Thiefin et al. 1990). The data of Browning et al. (2013) suggest a different interpretation to explain these findings, and the authors urge caution in the use of this technique. Happily, since the heyday of the use of this technique in the 1980s and 1990s, the advent of different technologies, including transgenic mice with specific receptor deletions, have, to a large extent, reinforced initial observations from the early work using perineural application of capsaicin. While past studies may have been overinterpreted, the central tenet that the vagal afferent pathway plays a crucial role in the control of GI function and food intake remains vindicated.