Selective activation of nociceptor sub-groups by slow depolarizing electrical stimuli

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Recent development of electrical stimulation paradigms enables specific assessment of unmyelinated nociceptors. A single pulse of halfsine wave shape (0.2 – 1 mA, 500 ms) induces in „polymodal“ nociceptors a volley-like discharge (“burst”) of action potentials (APs). Oscillating sine wave stimuli (0.05 – 0.2 mA, 4 Hz) additionally activate „mechano-insensitive“ („silent“) C-nociceptors. Upon continuous sine wave stimulation (1 min, 4 Hz), about 50% of patients with small-fiber neuropathy report increasing pain whereas healthy control subjects reveal a substantial pain accommodation. The proposed research project targets to identify the neurobiological mechanisms that enable „polymodal“ nociceptors to discharge with AP bursts. Mechanisms for ongoing nociceptor discharges without accommodation upon continuous sine wave stimulation will be assessed. Clinically relevant nociceptor sensitization as potential source for ongoing spontaneous pain together with local analgetic therapy will be recorded in neuropathic pain patients. Nociceptor classes contributing to secondary hyperalgesia will be identified.Single nerve fiber recordings will be performed in pig in vivo and compound action potentials (CAP) recorded ex vivo to explore the excitability of unmyelinated afferent neurons to strength-duration dependent halfsine wave pulses (chronaxie). Accommodation of nociceptors to continuous sine wave stimulation will be assessed in UVB inflamed skin of the N.saphenous innervation territory in pigs. The functional role of low-threshold voltage-gated calcium channels and calcium-activated chloride channels in nociceptor depolarization upon slowly increasing ramp currents will be explored.Similar to single nerve fiber recordings in pig, in human psycho-physics we will assess in healthy volunteers and neuropathic pain patients the neuronal excitation of unmyelinated afferents during continuous sine wave and strength-duration (chronaxie) halfsine wave stimulation. Excitability tests in patients serving as predictive value for local analgesic therapy and patient stratification will be explored. The differential contribution of „polymodal“ and „silent“ nociceptors on pain accommodation during ongoing nociceptor stimulation will be investigated in NGF-sensitized skin. Their contribution to secondary hyperalgesia and differential location in the skin will be identified. From the findings we expect indications on the mechanisms leading to sustained nociceptor excitation and discharge bursts, as well as the specific nociceptor classes involved in secondary hyperalgesia development. The results obtained from chronic neuropathic pain patients allow perspectives for a better patient stratification and the potential of a local analgesic treatment therapy.