Although more acute in some areas of the body than in others, temperature sensitivity is assumed to be present throughout the skin. Only when very small stimuli have been used (e.g., approximately 1 mm2) has sensitivity to warming or cooling appeared discontinuous. Here we report the discovery of patches of skin several square centimeters in area within which heating cannot be detected until skin temperature exceeds the thresholds of C heat-sensitive nociceptors (>41 degrees C). These warmth-insensitive fields (> or = 5 cm2), which appear to lack low-threshold warm fibers, were also found to have reduced responsiveness to non-painful heating and significantly higher heat pain thresholds compared to surrounding areas of skin. The existence of such sites corroborates reports that warm fibers are rare in human cutaneous nerves and confirms the classical theory that cutaneous innervation by the warmth sense is punctate and sparse. The insensitive areas also provide unique opportunities for assessing the contribution of the low-threshold warmth system to perception of heat and heat pain, and their existence in healthy young adults contraindicates use of warmth sensitivity in neurological assessments of C-fiber function.

Chronic low back pain (CLBP) and obesity are interrelated, but the physiological mechanisms linking the 2 conditions remain to be determined. Functional brain imaging data from CLBP patients show functional and structural alterations in areas mediating the attribution of hedonic value to food. Accordingly, we hypothesized that CLBP patients would exhibit alteration in the hedonic perception of highly palatable, calorie-containing foods. CLBP patients and matched healthy controls initially rated their perception of highly palatable puddings of varying fat content and sugary drinks of varying sucrose content without ingesting significant amounts of either stimulus. In a subsequent intake test, hungry participants ingested their preferred pudding ad libitum. Compared to healthy controls, CLBP patients exhibited significantly lower ratings of food pleasure when sampling the fat puddings but not when sampling the sugary drinks. In contrast, the patients' sensory evaluation of these stimuli was not different from those of healthy controls. In addition, whereas in healthy controls caloric intake from pudding closely matched hedonic ratings and decreased hunger after ad libitum pudding intake, such effect was totally abolished in CLBP patients. Our data thus reveal a decoupling between hedonic perception and fat calorie intake in CLBP patents, suggesting altered hedonic perception of fat as a potential mechanism linking CLBP to overeating and obesity.

The present study was undertaken to characterize further the structure and function of cutaneous nerves which we have previously shown to associate with skin immune cells (Hosoi et al., Nature 1993: 363:159). Ultrastructurally, axons were prominent within the superficial dermis and epidermis in neonatal murine skin, but they were inconspicuous in adult murine and primate skin. Immunohistochemical and immunoultrastuctural evaluation of normal adult human and simian skin for neural cell adhesion molecule (N-CAM), however, defined a plexus of axons surrounding superficial dermal mast cells and extending as delicate, vertical branches into the overlying epidermal layer. Antibodies to neuropeptides substance P, calcitonin gene-related peptide, and to nerve cell-specific clathrin (LCb subunit) also reacted with this neural plexus. Double labeling disclosed intimate associations of N-CAM-positive axons with dermal chymase-positive mast cells as well as with epidermal CD1a-positive Langerhans' cells by confocal scanning laser microscopy. Functionally, capsaicin applied to forearm skin revealed by 6 h discharge of mast cell chymase and induction of E-selectin in adjacent microvascular endothelium, events consistent with release of substance P from axons and subsequent stimulation of cytokine-mediated mast cell-endothelial interaction. Identical application of capsaicin to human skin xenografted to immunodeficient mice, and thus experimentally lacking in unmyelinated axons, failed to show similar findings. These results provide additional support to the concept that an elaborate network of cutaneous axons may play a functional role in regulation of skin inflammation and immunity.

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