title: IL-4 deficiency is associated with mechanical hypersensitivity in mice.
abstract: 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.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany. ueceyler_n@klinik.uni-wuerzburg.de
authors.forename: Nurcan
authors.initials: N
authors.lastname: Üçeyler
authors.forename: Tengü
authors.initials: T
authors.lastname: Topuzoğlu
authors.forename: Peter
authors.initials: P
authors.lastname: Schiesser
authors.forename: Saskia
authors.initials: S
authors.lastname: Hahnenkamp
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
mesh_terms: D000700:Analgesics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000175:diagnosis / Q000235:genetics*; D016753:Interleukin-10 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000175:diagnosis / Q000235:genetics*; D017933:Peripheral Nervous System / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000700:Analgesics; D018793:Interleukin-13; D053583:Interleukin-1beta; D011957:Receptors, Opioid; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4