Peripheral transient receptor potential vanilloid type 4 hypersensitivity contributes to chronic sickle cell disease pain

Abstract

Debilitating pain affects the lives of patients with sickle cell disease (SCD). Current pain treatment for patients with SCD fail to completely resolve acute or chronic SCD pain. Previous research indicates that the cation channel transient receptor potential vanilloid type 4 (TRPV4) mediates peripheral hypersensitivity in various inflammatory and neuropathic pain conditions that may share similar pathophysiology with SCD, but this channel's role in chronic SCD pain remains unknown. Thus, the current experiments examined whether TRPV4 regulates hyperalgesia in transgenic mouse models of SCD. Acute blockade of TRPV4 alleviated evoked behavioral hypersensitivity to punctate, but not dynamic, mechanical stimuli in mice with SCD. TRPV4 blockade also reduced the mechanical sensitivity of small, but not large, dorsal root ganglia neurons from mice with SCD. Furthermore, keratinocytes from mice with SCD showed sensitized TRPV4-dependent calcium responses. These results shed new light on the role of TRPV4 in SCD chronic pain and are the first to suggest a role for epidermal keratinocytes in the heightened sensitivity observed in SCD.

Schwann cell release of p11 induces sensory neuron hyperactivity in Fabry disease

“…Current-clamp recordings: Isolated sensory neuron somata were superfused with extracellular buffer (140 NaCl, Current-evoked excitability: Neuron somata were held at -70mV and intrinsic excitability was recorded using the following protocols [90]: (1) Voltage-current (V-I) relations were obtained using 20 sweeps of 500 ms alternating ascending/descending current pulses (5 pA steps from holding current). The plateau voltage deflection was plotted against current amplitude, and input resistance was determined from the slope of an IV plot.…”