IL-4 Deficiency Is Associated with Mechanical Hypersensitivity in Mice

Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C

BACKGROUND: N-methyl-D-aspartate (NMDA)-receptor activation contributes to postoperative hyperalgesia. Studies in volunteers have shown that intravenous local anaesthetics (LAs) prevent the development of hyperalgesic pain states. One potential explanation for this beneficial effect is the inhibition of NMDA receptor activation. Therefore, we studied the effects of LA on NMDA receptor function. METHODS: The human NR1A/NR2A NMDA receptor was expressed recombinantly in Xenopus laevis oocytes. Peak currents were measured by voltage clamp in Mg- and Ca2+-free, Ba2+-containing Tyrode's solution. Holding potential was -70 mV. Oocytes were stimulated with glutamate/glycine (at EC50) with or without 10 min prior incubation in bupivacaine, levobupivacaine, S-(-)-ropivacaine, or lidocaine (all at 10(-9)-10(-4) M), procaine (10(-4) M), R-(+)-ropivacaine (10(-4) M), QX314 (permanently charged, 5 x 10(-4) M) extracellularly or intracellularly or benzocaine (permanently uncharged, 5 x 10(-3) M). We also determined the effect of the protein kinase C (PKC) inhibitors chelerythrine (5 x 10(-5) M), calphostin C (3 x 10(-6) M) and Ro 31-8220 (10(-7) M), and the effect of PKC activation with phorbolester (10(-6) M). RESULTS: Non-injected oocytes were unresponsive to agonist application, but oocytes expressing NMDA receptors responded with inward currents (1.1+/-0.08 microA). All LA concentration-dependently inhibited agonist responses. The inhibition was reversible and stereoselective. Intracellular QX314 reduced responses to 59% of control, but extracellular QX314 was without effect. Benzocaine reduced responses to 33% of control. PKC inhibitors had no additional inhibitory effect beyond that of bupivacaine. The effect of PKC activation was abolished in the presence of bupivacaine. CONCLUSION: All LA tested inhibited the activation of human NMDA receptors in a concentration dependent fashion. This effect may contribute to reduced hyperalgesia and opiate tolerance observed after systemic administration of LA. The effect is independent of the charge of LA; site of action is intracellular. The mechanism of action may be mediated by inhibition of PK