Activity-dependent slowing of conduction velocity (ADS) differs between classes of human nociceptors. These differences likely reflect particular expression and use-dependent slow inactivation of axonal ion channels and other mechanisms governing axonal excitability. In this study, we compared ADS of porcine and human cutaneous C-fibers. Extracellular recordings were performed from peripheral nerves, using teased fiber technique in pigs and microneurography in humans. We assessed electrically-induced conduction changes and responsiveness to natural stimuli. In both species, the group of mechano-insensitive C-fibers showed the largest conduction slowing ( approximately 30%) upon electrical stimulation (2Hz for 3min). In addition, we found mechano-insensitive cold nociceptors in pig that slowed only minimally (<10% at 2Hz), and a similar slowing pattern was found in some human C-fibers. Mechano-sensitive afferents showed an intermediate conduction slowing upon 2Hz stimulation (pig: 14%, human 23%), whereas sympathetic efferent fibers in pig and human slowed only minimally (5% and 9%, respectively). In fiber classes with more pronounced slowing, conduction latencies recovered slower; i.e. mechano-insensitive afferents recovered the slowest, followed by mechano-sensitive afferents whereas cold nociceptors and sympathetic efferents recovered the fastest. We conclude that mechano-insensitive C-fiber nociceptors can be differentiated by their characteristic pattern of ADS which are alike in pig and human. Notably, cold nociceptors with a distinct ADS pattern were first detected in pig. Our results therefore suggest that the pig is a suitable model to study nociceptor class-specific changes of ADS.

3 H]-resiniferatoxin (RTX) binding assay utilizing rat spinal cord membranes was employed to identify novel vanilloids in a collection of natural products of fungal origin. Of the ®ve active compounds found (scutigeral, acetyl-scutigeral, ovinal, neogrifolin, and methyl-neogrifolin), scutigeral (K i =19 mM), isolated from the edible mushroom Albatrellus ovinus, was selected for further characterization. 2 Scutigeral induced a dose-dependent 45 Ca uptake by rat dorsal root ganglion neurons with an EC 50 of 1.6 mM, which was fully inhibited by the competitive vanilloid receptor antagonist capsazepine (IC 50 =5.2 mM).]-RTX binding isotherms were shifted by scutigeral (10 ± 80 mM) in a competitive manner. The Schild plot of the data had a slope of 0.8 and gave an apparent K d estimate for scutigeral of 32 mM. 4 Although in the above assays scutigeral mimicked capsaicin, it was not pungent on the human tongue up to a dose of 100 nmol per tongue, nor did it provoke protective wiping movements in the rat (up to 100 mM) upon intraocular instillation. 5 In accord with being non-pungent, scutigeral (5 mM) did not elicit a measurable inward current in isolated rat dorsal root ganglion neurons under voltage-clamp conditions. It did, however, reduce the proportion of neurons (from 61 to 15%) that responded to a subsequent capsaicin (1 mM) challenge. In these neurons, scutigeral both delayed (from 27 to 72 s) and diminished (from 5.0 to 1.9 nA) the maximal current evoked by capsaicin. 6 In conclusion, scutigeral and its congeners form a new chemical class of vanilloids, the triprenyl phenols. Scutigeral promises to be a novel chemical lead for the development of orally active, nonpungent vanilloids.

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