Laser-evoked potentials mediated by mechano-insensitive nociceptors in human skin.

OBJECTIVES: Laser-evoked potentials (LEP) were assessed after peripheral nerve block of the lateral femoral cutaneous nerve (LFCN) in healthy volunteers from partially anesthetized skin areas to differentially stimulate mechano-insensitive nociceptors. METHODS: An ultrasound-guided nerve block of the LFCN was performed in 12 healthy male subjects with Ropivacain 1%. After 30 min, the nerve block induced significantly larger anesthetic areas to mechanical stimuli than to electrical stimuli revealing an area of differential sensitivity. LEPs, reaction times and pain ratings were recorded in response to the laser stimuli of (1) completely anesthetic skin, (2) mechano-insensitive, but electrically excitable skin ('differential sensitivity'), (3) normal skin. RESULTS: LEP latencies in the area of differential sensitivity were increased compared to unaffected skin (228 ± 8.5 ms, vs. 181 ± 3.6 ms, p < 0.01) and LEP amplitudes were reduced (14.8 ± 1.2 µV vs. 24.6 ± 1.7 µV, p < 0.01). Correspondingly, psychophysically assessed response latencies in the differentially anesthetic skin were increased (649 ms vs. 427 ms, p < 0.01) and pain ratings reduced (1.5/10 vs. 5/10 NRS, p < 0.01). CONCLUSION: The increase in LEP latency suggests that mechano-insensitive heat-sensitive Aδ nociceptors (MIA, type II) have a slower conduction velocity or higher utilization time than mechano-sensitive type II Aδ nociceptors. Moreover, widely branched, slowly conducting and mechano-insensitive branches of Aδ nociceptors can explain our finding. LEPs in the differentially anesthetized skin provide specific information about a mechanically insensitive but heat-sensitive subpopulation of Aδ nociceptors. These findings support the concept that A-fibre nociceptors exhibit a similar degree of modality specificity as C-fibre nociceptors.

Mechano-sensitive nociceptors are required to detect heat pain thresholds and cowhage itch in human skin.

BACKGROUND: Mechano-sensitive and mechano-insensitive C-nociceptors in human skin differ in receptive field sizes and electrical excitation thresholds, but their distinct functional roles are yet unclear. METHODS: After blocking the lateral femoral cutaneous nerve (NCFL) in eight healthy male subjects (3-mL Naropin(®) 1%), we mapped the skin innervation territory being anaesthetic to mechanical pin prick but sensitive to painful transcutaneous electrical stimuli. Such 'differentially anaesthetic zones' indicated that the functional innervation with mechano-sensitive nociceptors was absent but the innervation with mechano-insensitive nociceptors remained intact. In these areas, we explored heat pain thresholds, low pH-induced pain, cowhage- and histamine-induced itch, and axon reflex flare. RESULTS: In differentially anaesthetic skin, heat pain thresholds were above the cut-off of 50°C (non-anaesthetized skin 47 ± 0.4°C). Pain ratings to 30 µL pH 4 injections were reduced compared to non-anaesthetized skin (48 ± 9 vs. 79 ± 6 VAS; p < 0.01). The axon reflex flare area did not differ between these zones (7.8 ± 1.4 cm(2) vs. 8.3 ± 0.5 cm(2) ). Histamine iontophoresis still caused pruritus in differentially anaesthetized skin in five of eight subjects (VAS 26 ± 14), whereas itch upon cowhage spicules was absent (VAS 0 vs. 29 ± 11 in non-anaesthetized skin). CONCLUSIONS: We conclude that activation of mechano-insensitive nociceptors is sufficient to provoke itch by histamine- and acid-induced pain. The mechano-sensitive nociceptors are crucial for cowhage-induced itch and for the assessment of heat pain thresholds.

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. Transient receptor potential ankyrin 1 (TRPA1) is up-regulated by NGF and chemical responsiveness to cinnamon aldehyde (TRPA1 agonist) was quantified. METHODS: Eight healthy volunteers received 1 µg human recombinant NGF (i.d. 50 µL) to L4/L5 processi spinosi skin. Mechanical, thermal and electrical sensitization was assessed at 3-6 h and at days 1, 2, 3, 5, 7, 10, 14 and 21, and pain upon cinnamon aldehyde (20%, 60 µL) recorded at days 3 and 21. RESULTS: Heat hyperalgesia developed with an initial maximum at 3 h [heat pain threshold -3.9°; peak pain ratings +22 visual analogue scale (VAS)] that decreased by day 1, subsequently increased to a maximum around day 5 (-5 ± 0.2 °C, +41 ± 4 VAS), and thereafter declined to ∼20% at day 21. Mechanical and electrical hyperexcitability developed within 3 days and gradually increased to peak between days 14 and 21. Pain intensity upon cinnamon aldehyde stimulation was doubled at the NGF site at day 3 and was still increased by about 50% at day 21. CONCLUSIONS: NGF causes immediate heat hyperalgesia probably linked to an up-regulation and sensitization of transient receptor potential vanilloid 1 and possibly other proteins involved in heat transduction. The delayed mechanical hyperalgesia is apparently independent of the time required for axonal transport of NGF receptor complexes. Local mRNA translation at axonal terminals and protein accumulation is hypothesized being involved in sustained NGF-evoked hyperalgesia.

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. Pain thresholds, electrically induced axon reflex erythema and pain (1.5-fold pain threshold, 5-100 Hz) was analysed at days 22, 24, 28, 35, 49 and 70 and correlated to hyperalgesia and spontaneous pain. RESULTS: Electrical pain threshold after combined NGF/UVB was reduced below single treatment at 24 h but not at 72 h post-UV-B irradiation. At the NGF/UV-B site, electrical pain was enhanced at all frequencies compared with single NGF and UV-B sites at 24 and 72 h with pain ratings exceeding control values about twofold to threefold [65 ± 7 vs. 25 ± 8 visual analogue scale (VAS) (24 h) and 55 ± 9 vs. 22 ± 5 VAS (72 h)]. Hyperalgesia to electrical stimulation correlated with hyperalgesia to pinprick (Spearman r = 0.44; p < 0.001, Bonferroni corr.) and supra-threshold heat (Spearman r = 0.55; p < 0.001) stimulation at 24 h only. Electrical pain thresholds at the NGF/UV-B site weakly correlated to spontaneous pain levels (Spearman r = 0.3; p = 0.025, without Bonferroni correction). In contrast, electrically induced pain or axon reflex erythema did not correlate to spontaneous pain levels. CONCLUSIONS: The combination of NGF and UV-B increases axonal excitability that contributes to hyperalgesia and might also facilitate ongoing spontaneous pain.

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% (∼0.4 mM) and 0.1% (∼4 mM) to both NGF and control skin sites. NGF caused a maximum reduction of heat pain thresholds at day 7 (NGF 42.6 ± 0.6 vs. 49.4 ± 0.3 °C in control skin). Lidocaine sensitized normal skin for heat pain, but reduced heat hyperalgesia after NGF at day 7 (44.3 ± 0.8 °C, lidocaine 0.1%; p < 0.005). Pain upon supra-threshold mechanical impact stimulation was increased after NGF at day 7 (VAS 29 + 5) and massively enhanced at day 21 (VAS 64 + 5, p < 0.001). Lidocaine dose-dependently attenuated mechanically-induced pain at both control and NGF-treated sites. Maximum lidocaine effects on mechanical hyperalgesia were recorded at day 21 in NGF skin (pain reduction to VAS 37 ± 4, p < 0.00001). Repetitive impact stimuli caused increasingly more pain at the NGF sites at day 21 and this pain increase was efficiently suppressed by lidocaine 0.1%. Lidocaine differentially affects NGF-induced mechanical hyperalgesia (analgesic effect) and heat sensitivity of nociceptors (sensitizing effect). These opposing responses may be attributed to block of sodium channels vs. sensitization of TRPV1. NGF-evoked extreme mechanical impact pain indicates high action potential discharge frequencies, which might be more susceptible to lidocaine block.

The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children.

BACKGROUND: Specific immunotherapy (SIT) and treatment with anti-immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or combined treatment. OBJECTIVE: A randomized, double-blind, placebo-controlled trial was conducted to compare the efficacy of single and combined treatment with SIT and anti-IgE (Omalizumab) in reducing symptom severity and rescue medication use. METHODS: A total of 221 subjects with birch and grass pollen allergic rhinoconjunctivitis aged 6-17 years were analysed during the grass pollen season. Group A (SITbirch + placebo) served as a reference group obtaining no effective treatment for grass pollen allergy. Group B received anti-IgE monotherapy during grass pollen season, group C SIT grass pollen monotherapy, and group D the combined treatment of SIT and Omalizumab. RESULTS: Preseasonal treatment with grass pollen SIT alone compared with SIT with the nonrelated allergen did not reduce symptoms or rescue medication use. Anti-IgE monotherapy significantly diminished rescue medication use and number of symptomatic days. The combined treatment with SIT and anti-IgE showed superior efficacy on symptom severity compared with anti-IgE alone. CONCLUSIONS: Co-seasonal Omalizumab therapy showed considerable effects in children with seasonal allergic rhinitis. The combination of SIT plus Omalizumab was clinically superior to each treatment alone during the first year of observation.