Mechanical sensitization, increased axonal excitability, and spontaneous activity in C-nociceptors after ultraviolet B irradiation in pig skin.

Ultraviolet B (UVB) irradiation induces hyperalgesia in human and animal pain models. We investigated mechanical sensitization, increase in axonal excitability, and spontaneous activity in different C-nociceptor classes after UVB in pig skin. We focused on units with receptive fields covering both irradiated and nonirradiated skin allowing intraindividual comparisons.

Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig.

Key Points: C-nociceptors are generally assumed to have a low maximum discharge frequency of 10-30 Hz. However, only mechano-insensitive 'silent' C-nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C-nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation.

TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors.

Pronounced activity-dependent slowing of conduction has been used to characterize mechano-insensitive, "silent" nociceptors and might be due to high expression of Na1.8 and could, therefore, be characterized by their tetrodotoxin-resistance (TTX-r). Nociceptor-class specific differences in action potential characteristics were studied by: (i) calcium imaging in single porcine nerve growth factor (NGF)-responsive neurites; (ii) extracellular recordings in functionally identified porcine silent nociceptors; and (iii) patch-clamp recordings from murine silent nociceptors, genetically defined by nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) expression.

Nerve growth factor locally sensitizes nociceptors in human skin.

Nerve growth factor (NGF) injected into the human skin causes local hyperalgesia to mechanical and electrical stimuli lasting for weeks. Pig data suggested axonal sensitization of C-nociceptors as a contributing mechanism. Here, we recorded single C-nociceptors in 11 human subjects 3 weeks after intracutaneous injection of 1 μg NGF into the foot dorsum.

C-fiber recovery cycle supernormality depends on ion concentration and ion channel permeability.

Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed.

Comparison of nerve growth factor-induced sensitization pattern in lumbar and tibial muscle and fascia.

Introduction: Nerve growth factor (NGF) induces profound hyperalgesia. In this study we explored patterns of NGF sensitization in muscle and fascia of distal and paraspinal sites.

Methods: We injected 1 µg of NGF into human (n = 8) tibialis anterior and erector spinae muscles and their fasciae.

Differential time course of NGF-induced hyperalgesia to heat versus mechanical and electrical stimulation in human skin.

Background: Nerve growth factor (NGF) causes early heat and delayed mechanical hyperalgesia. Axonal transport might contribute to lasting responses. Temporal hyperalgesia development was investigated by administering NGF in paraspinal skin.

Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study.

Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres.

Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors.

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers.

Axonal hyperexcitability after combined NGF sensitization and UV-B inflammation in humans.

Background: Both nerve growth factor (NGF) and ultraviolet-B (UV-B) irradiation sensitize nociceptive nerve endings and increase axonal excitability of nociceptors. Combining NGF and UV-B treatment is supra-additive for sensory sensitization and even caused spontaneous pain in about 70% of the subjects.

Methods: UV-B irradiation was performed at day 21 after intradermal NGF injection in 13 volunteers.

Inflammation meets sensitization--an explanation for spontaneous nociceptor activity?

Anti-nerve growth factor (anti-NGF) treatment is analgesic in chronic inflammatory pain conditions without reducing inflammation. Hypothesizing that ongoing pain induced by inflammatory mediators is increased by long term sensitization of nociceptors, we combined the non-inflammatory NGF-sensitization model with an inflammatory ultraviolet-B (UV-B) model in human volunteers. UV-B irradiation of the skin presensitized with NGF 3 weeks before intensified the pre-existing NGF hyperalgesia during the inflammatory phase of UV-B and caused spontaneous pain in about 70% of the subjects.

Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density.

Nerve growth factor (NGF) is involved in the long-term sensitization of nociceptive processing linked to chronic pain. Functional and structural ("sprouting") changes can contribute. Thus, humans report long-lasting hyperalgesia to mechanical and electrical stimulation after intradermal NGF injection and NGF-induced sprouting has been reported to underlie cancer bone pain and visceral pain.

Differential effects of low dose lidocaine on C-fiber classes in humans.

Unlabelled: The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. Voltage-gated sodium channels are crucial for action potential generation and conduction, and their availability controls the amount of activity-dependent conduction velocity slowing. This important axonal property, as assessed by microneurography, is used to differentiate human mechanoinsensitive (silent) nociceptors from the classical polymodal nociceptors.

NGF-evoked sensitization of muscle fascia nociceptors in humans.

Nerve growth factor (NGF) induces local hyperalgesia for a few days after intramuscular injection, but longer-lasting muscle pain upon systemic administration. As the muscle fascia is densely innervated by free nerve endings, we hypothesized a lasting sensitization of fascia nociceptors by NGF. We administered 1 μg NGF (dissolved in 100 μL saline) ultrasound-guided to the fascia of the Musculus erector spinae muscle at the lumbar level of 14 male volunteers and assessed hypersensitivity after 6 hours, and 1, 3, 7, 14, and 21 days.

The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo.

Background: Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation).

Methods: Single-fiber extracellular recordings from saphenous nerves were performed.

Differential effects of lidocaine on nerve growth factor (NGF)-evoked heat- and mechanical hyperalgesia in humans.

We investigated the effects of a non-specific sodium channel blocker (lidocaine) on heat pain thresholds and mechanical impact pain at day 7 and 21 after intradermal injection of 1 μg NGF. Measurements were performed in 12 healthy male subjects prior to and 5 min after intradermal injection of 150 μl lidocaine administered at concentrations of 0.01% (∼0.

Double spikes to single electrical stimulation correlates to spontaneous activity of nociceptors in painful neuropathy patients.

Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity.

Nerve growth factor selectively decreases activity-dependent conduction slowing in mechano-insensitive C-nociceptors.

Nerve growth factor (NGF) induces acute sensitization of nociceptive sensory endings and long-lasting hyperalgesia. NGF modulation of sodium channel expression might contribute to neurotrophin-induced hyperalgesia. Here, we investigated NGF-evoked changes of the activity-dependent slowing of conduction in porcine C-fibers.

NGF enhances electrically induced pain, but not axon reflex sweating.

High-affinity receptors for nerve growth factor (NGF) are found on nociceptors and sympathetic efferents. NGF is known to sensitize nociceptors, increase innervation density, and fire frequency of sympathetic fibers. We explored axonal sensitization of afferent and efferent fibers following intracutaneous injection of NGF in human and pig skin.

Nerve growth factor-evoked nociceptor sensitization in pig skin in vivo.

Peripheral sensitization of skin nociceptors by nerve growth factor (NGF) was explored in pig skin in vivo. As an objective output measure, the area of axon-reflex-mediated erythema was assessed upon mechanical, thermal, chemical, and electrical stimuli delivered at 1, 3, and 7 days after i.d.

NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin.

Nerve growth factor (NGF) modulates sensitivity and sprouting of nociceptors. We explored the spatial and temporal sensitization induced by NGF injection (1 microg) in human skin. Hyperalgesia was investigated in 16 volunteers (36+/-9 years) at day 1, 3, 7, 21, and 49.

Patterns of activity-dependent conduction velocity changes differentiate classes of unmyelinated mechano-insensitive afferents including cold nociceptors, in pig and in human.

Activity-dependent slowing of conduction velocity (ADS) differs between classes of human nociceptors. These differences likely reflect particular expression and use-dependent slow inactivation of axonal ion channels and other mechanisms governing axonal excitability. In this study, we compared ADS of porcine and human cutaneous C-fibers.

Single-fiber recordings of unmyelinated afferents in pig.

Microneurography has provided valuable data on single-fiber characteristics in healthy volunteers and patients, featuring a unique setting that allows linking discharge of single fibers to percept. This advantage is of particular value, when pain patients are examined. Latest results on specific changes of axonal excitability differentially expressed in various C-fiber classes have incited studies linking axonal excitability changes to the mechanism of chronic pain.