Robert P. Tuckett

Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons

The purpose of this study was to determine which myelinated cutaneous receptor populations in cat are responsive to a stimulus (cowhage) that produces unambiguous pruritus in human subjects. Initial experiments using electrocutaneous stimuli demonstrated that fibers conducting as slowly as 1.5 m/s could be recorded from small fascicles of cutaneous nerves. Multiunit recordings from fascicles and nerve filaments revealed small, but significant changes in nerve firing following application of cowhage. A sample of all known myelinated receptor populations showed that each gave a response that was less than its response to adequate intensities of mechanical stimulation (n = 118). It was concluded that the slight changes in multunit discharge induced by cowhage could be accounted for by changes in mechanoreceptor behavior and hence there was no evidence to support the possibility that an unknown population of myelinated sensory fibers exists that signals pruritus. The possibility that itch is signaled by coactivation of myelinated mechanoreceptive and C-polymodal nociceptive neurons was discussed.

Substance P axons and sensory threshold increase in burn-graft human skin

BACKGROUND Our knowledge of afferent nerve fiber reinnervation of grafted skin following third-degree burn is limited by a lack of quantitative histological and psychophysical assessment from the same cutaneous area. The current study compares fiber profile and functional recovery measurements in injured and control skin from the same subject. MATERIALS AND METHODS Nerve regeneration and modality-specific sensory thresholds were compared using immunocytochemical labeling with protein gene product 9.5 antibody to stain all axons and anti-substance P to label substance P axons (which are predominantly unmyelinated), as well as computerized instrumentation to obtain psychophysical estimates. RESULTS Compared to control skin, threshold measures of pinprick (P < 0.001), warming (P < 0.001), touch (P < 0.001), and vibration (P < 0.01) were significantly elevated in burn-graft skin and correlated with histological analysis of skin biopsies obtained from the same site. Immunohistochemical staining of all axons innervating the dermis and epidermis revealed a significant reduction in burn-graft relative to control skin (54% decrease, P < 0.0001). In contrast, the incidence of substance P nerve fibers was significantly elevated in burn-graft (177% increase, P < 0.05) and appeared to correlate with patient reports of pruritus and pain. CONCLUSIONS Observations support the hypothesis that sensory regeneration is fiber-size-dependent in burn-graft skin. The findings that substance P fiber growth increased while total fiber count decreased and that thermal threshold showed the greatest degree of functional recovery suggest that unmyelinated neurons have the greater ability to transverse scar tissue and reinnervate grafted skin following third-degree burn injury.

Rapid displacements of the skin lack clear positional information.

Rapid skin indentations can produce strong tap-like sensations that contain little information about skin indentation depth. Although slower stimuli produce weaker sensations, subjects can more accurately identify how the position of the skin surface changes with respect to the deeper tissues. This dissociation between intensity and depth information suggests that intensity and depth are served by different neural circuits.

Tactile testing device and methods

An automatic apparatus for testing tactile responses of a patient is disclosed. The embodiments of the invention variously include components for: applying a nonambient temperature to the patients skin to test the patients response to thermal stimuli; pricking the patients skin to test the patients response to pain; indenting the patients skin to test the patients response to touch; vibrating the patients skin to test the patients response to vibration; and for making two spaced apart contacts with the patients skin to test the patients two point discrimination response. A general purpose computer and dedicated control circuits function to control the operation of the system and record the responses of the patient. The embodiments of the present invention are able to repeatedly reproduce each test so that the tests carried out are reproducible and accomplished in a minimum of time.

Progress in Vibrotactile Threshold Evaluation Techniques: A Review

Vibrotactile threshold (VT) testing has been used for nearly a century to investigate activation of human somatosensory pathways. This use of vibrotactile stimuli provides a versatile tool for detecting peripheral neuropathies, and has been broadly used for investigation of carpal tunnel syndrome. New applications include investigation of drug-induced neuropathies and diabetes-related neuropathies. As a feedback device, the vibrotactile stimuli could be used as an information delivery system for rehabilitative feedback devices for upper limb musculoskeletal disorders or as information channels for the visually impaired. This review provides a comprehensive review of the advancement in VT measurement techniques over time and a comparison of these techniques in terms of various hardware features used and the testing protocols implemented. The advantages and limitations of these methods have been discussed along with specific recommendations for their implementation and suggestions for incorporation into clinical practice.

5-HT2 and 3 receptor antagonists suppress the response of rat type I slowly adapting mechanoreceptor: an in vitro study.

Previous experiments have shown an increase in rat type I mechanoreceptor responsiveness during arterial serotonin (5-hydroxytryptamine) infusion and the presence of serotonin immunostaining in Merkel cells. The current findings demonstrate that the 5-HT(2) antagonists ritanserin and ketanserin, as well as the 5-HT(3) antagonist MDL 72222, reduce type I response to a standardized mechanical stimulus in an in vitro skin preparation. In addition, ritanserin blocked the enhancement of type I response produced by 5-HT. These experiments suggest that serotonin is released during mechanical distortion of the Merkel cell membrane and alters action potential generation by the type I ending. In addition, it is possible that serotonin, released from outside the type I complex, influences mechanoreceptor responsiveness. For example, serotonin generated during inflammatory events could enhance type I response to mechanical stimulation and thereby increase symptoms of mechanical allodynia.

Response of Cat Ventrolateral Spinal Axons to an Itch-Producing Stimulus (Cowhage)

A comparison was made between different categories of mechanically sensitive, ventrolateral spinal axons to assess their sensitivity to the itch-producing substance cowhage. Of 52 wide-dynamic-range (WDR) units, 17 had contralateral, 22 had ipsilateral, and 13 had bilateral receptive fields. Of the 5 low-threshold units, 1 had an ipsilateral receptive field and the remainder were bilateral. Among the high-threshold units, 10 were contralateral, 6 ipsilateral, and 5 bilateral. Although there was no evidence of cowhage sensitivity in either low- or high-threshold spinal axons, neurons with WDR properties were reactive to cowhage. WDR neurons were subclassified on the basis of their resting discharge pattern as having intermittent, continuous, or no resting discharge. WDR units with an intermittent pattern of resting discharge demonstrated a significant sensitivity to active cowhage and hence might be regarded as pruritogen-responsive spinal axons. Inactive cowhage was used as a control stimulus. In some WDR units with large receptive fields, there were observations suggesting convergence of chemoreceptive and mechanoreceptive inputs, which produced inhibitory as well as excitatory effects.

Chemosensitivity of the Rat Type I Slowly Adapting Mechanoreceptor

An in vitro lateral thoracic skin preparation of the adult rat was used to test the effect of serotonin (5, 50, 500 μM) and control solutions on the response of the type I slowly adapting mechanoreceptor to a standard mechanical stimulus. Serotonin (5-HT) significantly increased the magnitude of the type I response to mechanical indentation: 50 μM 5-HT infusion enhanced responsiveness more effectively than 5 μM 5-HT. In the absence of mechanical stimulation, little or no change in spontaneous discharge relative to control was observed, and recovery to baseline levels occurred within three stimulus trials. In vitro and in vivo control experiments showed no statistically significant change in responsiveness over a similar number of stimulus cycles. It was concluded that 5-HT modulates, but does not activate the rat type I receptor or alter its ability to encode the depth and/or velocity of mechanical displacement.

Comparison of paclitaxel and cisplatin effects on the slowly adapting type I mechanoreceptor.

Cisplatin and paclitaxel are two of the most widely used chemotherapy drugs for the treatment of several forms of cancer. Both agents produce significant levels of peripheral neuropathy that can result in changes of treatment regimen. Although there have been recent efforts to understand the effects of these agents on nociceptor populations, little study has been made on their effects on large afferent populations. Here we report acute and chronic effects of paclitaxel and cisplatin administration on the type I mechanoreceptor using a skin-nerve preparation in rat and a standardized mechanical stimulus to compare mechanoreceptor response before and after treatment. In a control preparation, suppression of type I mechanoreceptor response during 2-min, arterial infusion of paclitaxel or cisplatin was significant for paclitaxel (28%, 1 microM; 33%, 10 microM; p<0.025), but not cisplatin (9%, 500 microM; 19%, 5 mM; p>0.05). Response returned to baseline within a 2-min washout period. Following pretreatment with paclitaxel or cisplatin, baseline response was significantly reduced from control animals. In addition, unlike the control preparation, a subsequent infusion of paclitaxel induced prolonged response suppression. Nerve fascicles innervating the preparation showed significant reduction in conduction velocity relative to control (cisplatin pretreatment: Abeta, 22%, p<0.01; C-fiber, 33%, p<0.01. paclitaxel pretreatment: Abeta, 17%, p<0.05; C-fiber, 23%, p<0.05). It was concluded that chronic paclitaxel or cisplatin treatment not only significantly alters the type I mechanotransduction process, but also increases susceptibility of the type I ending to further paclitaxel exposure.

A Novel Device to Evaluate the Vibrotactile Threshold

This paper presents the initial prototype design of a vibrotactile threshold evaluator for the workplace (VTEW), which is portable and configurable in terms of the probe diameter (2‐10 mm), applied frequency (1‐500 Hz), angle of probe (0‐120 deg), and displacement of probe (1‐1500 lm), and is operated with a customizable LABVIEW interface. The vibrotactile threshold is the minimum amplitude of vibration that is perceived at a particular frequency by a subject and is analogous to a hearing test. It can be used to evaluate neuropathy, for instance due to carpal tunnel syndrome or peripheral neuropathy secondary to diabetes. The vibrotactile threshold (VT) at 50 Hz was evaluated using VTEW and an established device, the Vibrotactile Tester (VTT). These results were compared for validation of VTEW. Each subject underwent Phalen’s and Tinel’s test, and the results of these clinical evaluations for carpal tunnel syndrome were used to classify subjects as symptomatic and asymptomatic. The results of the VTEW and the VTT were statistically similar and the age correction developed for both devices from this study were similar to the previously conducted studies. The mean VT values from the VTEW showed an increased VT for symptomatic subjects. The low frequency range of the VTEW was used to evaluate the VT at 4 Hz, and a comparison of VT at 4 Hz and 50 Hz showed a higher sensitivity of subjects to 50 Hz as compared to 4 Hz. The gender effect on VT was also studied and discussed, along with recommendation for further investigation. A novel and highly customizable device for testing the vibrotactile threshold is presented, with results demonstrating identification of symptomatic subjects. This device could be used to regularly test workers at risk for developing carpal tunnel syndrome (e.g. assembly line workers) to monitor for elevations in VT. Other applications include using the low frequency to evaluate peripheral neuropathy. [DOI: 10.1115/1.4006901]