Micropipette aspiration of the Pacinian corpuscle.

The Pacinian corpuscle (PC) is a cutaneous mechanoreceptor sensitive to high-frequency vibrations (20-1000Hz). The PC is of importance due to its integral role in somatosensation and the critical need to understand PC function for haptic feedback system development. Previous theoretical and computational studies have modeled the physiological response of the PC to sustained or vibrating mechanical stimuli, but they have used estimates of the receptor's mechanical properties, which remain largely unmeasured. In this study, we used micropipette aspiration (MPA) to determine an apparent Young's modulus for PCs isolated from a cadaveric human hand. MPA was applied in increments of 5mm H2O (49Pa), and the change in protrusion length of the PC into the pipette was recorded. The protrusion length vs. suction pressure data were used to calculate the apparent Young's modulus. Using 10 PCs with long-axis lengths of 2.99±0.41mm and short-axis lengths of 1.45±0.22mm, we calculated a Young's modulus of 1.40±0.86kPa. Our measurement is on the same order of magnitude as those approximated in previous models, which estimated the PC to be on the same order of magnitude as skin or isolated cells, so we recommend that a modulus in the kPa range be used in future studies.

Computational Parametric Analysis of the Mechanical Response of Structurally Varying Pacinian Corpuscles.

The Pacinian corpuscle (PC) is a cutaneous mechanoreceptor that senses low-amplitude, high-frequency vibrations. The PC contains a nerve fiber surrounded by alternating layers of solid lamellae and interlamellar fluid, and this structure is hypothesized to contribute to the PC's role as a band-pass filter for vibrations. In this study, we sought to evaluate the relationship between the PC's material and geometric parameters and its response to vibration. We used a spherical finite element mechanical model based on shell theory and lubrication theory to model the PC's outer core. Specifically, we analyzed the effect of the following structural properties on the PC's frequency sensitivity: lamellar modulus (E), lamellar thickness (h), fluid viscosity (µ), PC outer radius (Ro), and number of lamellae (N). The frequency of peak strain amplification (henceforth "peak frequency") and frequency range over which strain amplification occurred (henceforth "bandwidth") increased with lamellar modulus or lamellar thickness and decreased with an increase in fluid viscosity or radius. All five structural parameters were combined into expressions for the relationship between the parameters and peak frequency, ωpeak=1.605×10-6N3.475(Eh/µRo), or bandwidth, B=1.747×10-6N3.951(Eh/µRo). Although further work is needed to understand how mechanical variability contributes to functional variability in PCs and how factors such as PC eccentricity also affect PC behavior, this study provides two simple expressions that can be used to predict the impact of structural or material changes with aging or disease on the frequency response of the PC.

A multiphysics model of the Pacinian corpuscle.

The Pacinian corpuscle (PC) is a dermal mechanoreceptor that responds to high-frequency (20-1000 Hz) vibrations. The PC's structure allows transmission of vibrations through its layers (lamellae) to the centrally-located nerve fiber (neurite). This work combines mechanical models of the PC with an electrochemical model of peripheral nerves to simulate the tactile response of the entire system. A three-stage model of response to a vibratory input was developed, consisting of (1) outer core mechanics, (2) inner core mechanics, and (3) neurite electrochemistry. The model correctly predicts the band-pass nature of the PC's frequency response, showing that the PC structure can amplify oscillatory strains within its target frequency band. Specifically, strain induced by a vibratory stimulus is amplified by a factor of 8-12 from the PC surface to the neurite. Our results also support the hypothesis that PC rapid adaptation is affected by the lamellar structures without requiring neuronal adaptivity. Simulated different-sized PCs showed a shift in frequency response, suggesting that clusters of different-sized PCs could enable more nuanced tactile encoding than uniform clusters. By modeling the PC's mechano-to-neural transduction, we can begin to characterize the mechanosensation of other receptors to understand how multiple receptors interact to create our sensation of touch.

Multiscale Mechanical Model of the Pacinian Corpuscle Shows Depth and Anisotropy Contribute to the Receptor's Characteristic Response to Indentation.

Cutaneous mechanoreceptors transduce different tactile stimuli into neural signals that produce distinct sensations of touch. The Pacinian corpuscle (PC), a cutaneous mechanoreceptor located deep within the dermis of the skin, detects high frequency vibrations that occur within its large receptive field. The PC is comprised of lamellae that surround the nerve fiber at its core. We hypothesized that a layered, anisotropic structure, embedded deep within the skin, would produce the nonlinear strain transmission and low spatial sensitivity characteristic of the PC. A multiscale finite-element model was used to model the equilibrium response of the PC to indentation. The first simulation considered an isolated PC with fiber networks aligned with the PC's surface. The PC was subjected to a 10 µm indentation by a 250 µm diameter indenter. The multiscale model captured the nonlinear strain transmission through the PC, predicting decreased compressive strain with proximity to the receptor's core, as seen experimentally by others. The second set of simulations considered a single PC embedded epidermally (shallow) or dermally (deep) to model the PC's location within the skin. The embedded models were subjected to 10 µm indentations at a series of locations on the surface of the skin. Strain along the long axis of the PC was calculated after indentation to simulate stretch along the nerve fiber at the center of the PC. Receptive fields for the epidermis and dermis models were constructed by mapping the long-axis strain after indentation at each point on the surface of the skin mesh. The dermis model resulted in a larger receptive field, as the calculated strain showed less indenter location dependence than in the epidermis model.

Whiplash-like facet joint loading initiates glutamatergic responses in the DRG and spinal cord associated with behavioral hypersensitivity.

The cervical facet joint and its capsule are a common source of neck pain from whiplash. Mechanical hyperalgesia elicited by painful facet joint distraction is associated with spinal neuronal hyperexcitability that can be induced by transmitter/receptor systems that potentiate the synaptic activation of neurons. This study investigated the temporal response of a glutamate receptor and transporters in the dorsal root ganglia (DRG) and spinal cord. Bilateral C6/C7 facet joint distractions were imposed in the rat either to produce behavioral sensitivity or without inducing any sensitivity. Neuronal metabotropic glutamate receptor-5 (mGluR5) and protein kinase C-epsilon (PKCε) expression in the DRG and spinal cord were evaluated on days 1 and 7. Spinal expression of a glutamate transporter, excitatory amino acid carrier 1 (EAAC1), was also quantified at both time points. Painful distraction produced immediate behavioral hypersensitivity that was sustained for 7 days. Increased expression of mGluR5 and PKCε in the DRG was not evident until day 7 and only following painful distraction; this increase was observed in small-diameter neurons. Only painful facet joint distraction produced a significant increase (p<0.001) in neuronal mGluR5 over time, and this increase also was significantly elevated (p≤0.05) over responses in the other groups at day 7. However, there were no differences in spinal PKCε expression on either day or between groups. Spinal EAAC1 expression was significantly increased (p<0.03) only in the nonpainful groups on day 7. Results from this study suggest that spinal glutamatergic plasticity is selectively modulated in association with facet-mediated pain.

Development of a duration threshold for modulating evoked neuronal responses after nerve root compression injury.

Cervical nerve roots are susceptible to compression injuries of various durations. The duration of an applied compression has been shown to contribute to both the onset of persistent pain and also the degree of spinal cellular and molecular responses related to nociception. This study investigated the relationship between peripherally-evoked activity in spinal cord neurons during a root compression and the resulting development of axonal damage. Electrically-evoked spikes were measured in the spinal cord as a function of time during and after (post-compression) a 15 minute compression of the C7 nerve root. Compression to the root significantly (p=0.035) reduced the number of spikes that were evoked over time relative to sham. The critical time for compression to maximally reduce evoked spikes was 6.6±3.0 minutes. A second study measured the post- compression evoked neuronal activity following compression applied for a shorter, sub-threshold time (three minutes). Ten minutes after compression was removed, the discharge rate remained significantly (p=0.018) less than baseline by 58±25% relative to sham after the 15 minute compression, but returned to within 3±33% of baseline after the three minute compression. Axonal damage was evident in the nerve root at day seven after nerve root compression only after a 15 minute compression. These studies demonstrate that even a transient mechanical insult to the nerve root is sufficient to induce sustained neuronal dysfunction and axonal pathology associated with pain, and results provide support that such minor neural tissue traumas can actually induce long-lasting functional deficits.