Research reportLocal inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons
Introduction
Painful stimuli applied to the skin activate specific primary sensory neurons called nociceptors. Neurons with myelinated A-delta and unmyelinated C fibers are considered to be nociceptive neurons in mammals. Peripheral inflammation induced by plantar injection of a chemical irritant such as Freund’s complete adjuvant (CFA) can elicit acute hyperalgesia at the injection site and adjacent area. Electrophysiological studies show that inflammation increases the number of neurons with A-delta and C fibers that respond to ATP injection [16] and receptive field stimulation [14]. Therefore, the number of activated neurons must increase as well as the electrical excitability of individual neurons to cause behavioral hyperalgesia during inflammation.
Vanilloid receptor 1 (VR1) is a non-selective cation channel gated by noxious heat, proton and capsaicin [8], [28], that has recently been cloned [9], [12]. This receptor is essential for the development of thermal hyperalgesia, as mice lacking this receptor lack thermal hyperalgesia after inflammation [10]. Studies in vitro have shown that substances produced by local inflammation such as ATP [29], bradykinin [22] and NGF [11] can increase the capsaicin-evoked current in VR1 expressing cells. These functional modulations of VR1 channels, however, cannot explain why the number of active neurons increases after inflammation; novel recruitment of VR1 expression would be necessary.
In the present study, we postulated that inflammation increases VR1 positive neuronal profiles, which would cause the ratio of electrically activated neurons to increase. We therefore performed histochemical analyses to compare VR1 expression in DRG neurons between control and inflamed animals. We also double-stained VR1 with several neuronal markers to investigate whether or not inflammation can alter the expression of VR1 within heterogeneous DRG neurons. We found that peripheral inflammation can increase in VR1 positive neuronal profiles within specific subsets of DRG neurons.
Section snippets
Animals
All experiments were approved by the Kyoto Prefectural University of Medicine Animal Care Committee and were in accordance with National Institutes of Health Guide for the Care and Use of Laboratory Animals and guidelines of the International Association for the Study of Pain. Peripheral inflammation was generated by an intraplantar injection of Freund’s complete adjuvant (CFA; Sigma; 50 μl/each) into the left hind paws of eight male Sprague–Dawley rats, each weighing 200–250 g. A total of
VR1 expression in lumbar DRG
VR1-like immunoreactivity (LI) was detected within DRG neurons of both control and inflamed animals. In control animals, a total of 3300 DRG neurons were analyzed. Among them, 879 neurons were positive for VR-1. In inflamed animals, on the other hand, 1352 neurons were positive for VR1 among 3031 total neurons. Of DRG neurons, 27% were positive for VR1-LI in control animals. Compared with controls, these neurons were more frequently detected after inflammation (Fig. 1A), since the ratio of
Inflammation causes VR1 expression to increase
We detected DRG neurons that were positive for VR1-LI more frequently after local inflammation. The ratio of neurons expressing VR1 reached 1.5-fold the basal level, showing up-regulation of VR1 expression in DRG neurons in which VR1 was previously undetectable during inflammatory hyperalgesia. Recent studies show that levels of VR1-LI increase within nerve fibers at the site of inflammation in human and rodents [7], [34]. These and our results indicate that increased expression of VR1 in the
Acknowledgements
This work was supported by the NOVARTIS Foundation (Japan) for the Promotion of Science
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2018, Bioorganic and Medicinal ChemistryCitation Excerpt :In addition to exogenous agonists such as capsaicin, TRPV1 is activated by a number of functionally unrelated stimuli, such as protons, heat, and some endogenous vanilloids produced by inflamed tissues.2 The expression of TRPV1 is up-regulated in non-myelinated C-fibers as well as A-fibers under certain nerve injury and inflammatory disease conditions.3–5 Capsaicin, a well-known TRPV1 agonist, is clinically effective for treating a variety of neuropathic pain conditions, with its analgesic actions are thought to result from the inhibition of TRPV1 function by desensitization.