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Objectives: Previously, we found in cultures of primary neurons and in animals that sensitized primary neurons can be desensitized by treatment with e.g. beta-adrenergic receptor agonists. We now tested whether also in human sensitization such as UVB-radiation induced sunburn-like hyperalgesia can be reduced by intradermal injection of the beta-adrenergic receptor agonist terbutaline., Methods: In our prospective randomized study, 17 participants received an individual UVB dose to cause a defined local sunburn-like erythema at four locations, two on each forearm. Twenty-four hours later, the sensitized four areas were injected intradermally with terbutaline pH 4.3, terbutaline pH 7.0, saline pH 4.3 or saline pH 7.0, respectively. Pain thresholds were examined before and after induction of UVB-sensitization, and 15, 30 and 60 min after injection of the respective solution. Mechanical pain thresholds of the skin and of deeper tissues were determined by pinprick and pressure algometer measurements, respectively., Results: UVB-irradiation decreased mechanical pain thresholds for pinprick and pressure algometer measurements demonstrating a successful sunburn-like sensitization. Intradermal injection of terbutaline pH 7.0 into the sensitized skin reduced the sensitization for all measured timepoints as determined by pinprick measurements. Pinprick measurements of sensitization were not reduced by injection of terbutaline pH 4.3, saline solution pH 7.0 or saline solution pH 4.3. Also, sensitization of deeper tissue nociceptors were not altered by any of the injections as measured with the pressure algometer., Conclusions: Similar to our cellular observations, also in humans beta-adrenergic agonists such as terbutaline can reduce the sensitization of primary neurons in the skin., Significance: We previously showed in model systems that beta-adrenergic stimulation can not only sensitize but also desensitize nociceptors. Our study shows that also in humans beta-adrenergic agonists desensitize if injected into UVB-sensitized skin. This indicates an analgesic activity of adrenergic agonists in addition to their vasoconstrictory function., (© 2018 European Pain Federation - EFIC®.)

Background: Intrathecal/intracisternal BDNF in rodents produces long-lasting hyperalgesia/allodynia, which implies BDNF plays a role in the establishment and maintenance of central sensitization. Both self-regeneration of endogenous BDNF and neuroplastic modifications of spinal NMDA receptors downstream TrkB signalling could be involved in such enduring hyperalgesia. We investigated to what extent BDNF by itself could participate in the generation and maintenance of mechanical hyperalgesia using pharmacological tools., Methods: We studied sensitivity of mechanical hyperalgesia induced by a single intrathecal (i.t.) injection of BDNF (3 ng/10 μL i.t.) administered at time zero, for: (1) chronic NMDA receptor inhibition with subcutaneously implanted 7-day delivery osmotic pumps loaded with ketamine; (2) TrkB receptor inhibition with intraperitoneal (i.p.) cyclotraxine-B; and (3) chronic glial inhibition with repeated propentofylline i.t. injections. Nociceptive threshold to paw pressure, tested on days -3, 0, 3, 7, 10 and 14, was used as the index of central sensitization. Locomotor patterns and food and water consumption were assessed with LABORAS., Results: Chronic ketamine prevented the mechanical hyperalgesia induced by BDNF, without affecting locomotion and food and water consumption. After pump depletion, a late hyperalgesic response to paw pressure stimulation emerged, which can be lastingly antagonized by cyclotraxine-B. Chronic propentofylline treatment irreversibly suppressed BDNF-induced hyperalgesia., Conclusion: Activation of NMDA receptors downstream to TrkB signalling is essential for behavioural expression of the mechanical hyperalgesia induced by intrathecal BDNF. However, maintenance of the hyperalgesia depends mainly from self-regenerating glial BDNF rather than from a NMDA receptor-dependent form of neuroplasticity., Significance: Intrathecal BDNF induces long-lasting central sensitization via a glial-likely BDNF self-regenerating mechanism, whose behavioural expression depends on downstream activation of NMDA receptors. This knowledge suggests that TrkB antagonists could represent an interesting lead for the development of novel therapeutic strategies for some chronic pain conditions., (© 2017 European Pain Federation - EFIC®.)

Background: The UVB and heat rekindling (UVB/HR) model shows potential as a translatable inflammatory pain model. However, the occurrence of central sensitization in this model, a fundamental mechanism underlying chronic pain, has been debated. Face, construct and predictive validity are key requisites of animal models; electromyogram (EMG) recordings were utilized to objectively demonstrate validity of the rat UVB/HR model., Methods: The UVB/HR model was induced on the heel of the hind paw under anaesthesia. Mechanical withdrawal thresholds (MWTs) were obtained from biceps femoris EMG responses to a gradually increasing pinch at the mid hind paw region under alfaxalone anaesthesia, 96 h after UVB irradiation. MWT was compared between UVB/HR and SHAM-treated rats (anaesthetic only). Underlying central mechanisms in the model were pharmacologically validated by MWT measurement following intrathecal N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, or saline., Results: Secondary hyperalgesia was confirmed by a significantly lower pre-drug MWT {mean [±standard error of the mean (SEM)]} in UVB/HR [56.3 (±2.1) g/mm(2) , n = 15] compared with SHAM-treated rats [69.3 (±2.9) g/mm(2) , n = 8], confirming face validity of the model. Predictive validity was demonstrated by the attenuation of secondary hyperalgesia by MK-801, where mean (±SEM) MWT was significantly higher [77.2 (±5.9) g/mm(2) n = 7] in comparison with pre-drug [57.8 (±3.5) g/mm(2) n = 7] and saline [57.0 (±3.2) g/mm(2) n = 8] at peak drug effect. The occurrence of central sensitization confirmed construct validity of the UVB/HR model., Conclusions: This study used objective outcome measures of secondary hyperalgesia to validate the rat UVB/HR model as a translational model of inflammatory pain., (© 2014 The Authors European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

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.

Background: This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare., Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis., Results: Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy., Conclusion: Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction., (© 2013 European Federation of International Association for the Study of Pain Chapters.)