.: Scientific Highlight of the Year

Presented by:

Polish Neuroscience Society

Prof. Jolanta Skangiel - Kramska

3 Pasteura St.

02-093 Warsaw

Tel. 048 22 5892446

Email: j.kramska@nencki.gov.pl

Interleukin-1alpha has antiallodynic and antihyperalgesic activities in a rat neuropathis pain model

Joanna Mika, Michal Korostynski, Dorota Kaminska, Agnieszka Wawrzczak-Bargiela, Maria Osikowicz, Wioletta Makuch, Ryszard Przewlocki, Barbara Przewlocka
Pain 138(2008) 587-597

Summary:
What is the role of IL-1 in nociception under neuropathic pain conditions?
Longstanding neuropathic pain is one of the most challenging medical problems, because it's therapy is resistant for analgesic drug treatment. Clinical neuropathic pain syndrome can develop as a result of damage to nerves due to accidents, tumors, diabetic, herpes zoster, AIDS, sclerosis multiplex, hypoxia, stroke. An understanding of how neuropathic pain develops is necessary to guide development of new pain therapies, There is increasing evidence that glia play a crucial role in central nervous system function and activated release various interleukins (ILs) that act on neurons to alter their function. Cytokines like IL-6 have been suggested to be common mediators of allodynia and hyperalgesia; those like IL-10 are associated with abolished neuropathic pain symptoms. In contrast to the large number of studies on IL-6 and IL-10, relatively little was known about the role of the IL-1 family in nociceptive processing. The IL-1 family includes IL-1alpha and IL-1beta, which bind to the IL-1-type 1 receptor and the IL-1 receptor accessory protein. IL-1beta is one of the principal pro-inflammatory cytokines released in response to damage. Elevated levels of IL-1beta have been implicated in chronic neurodegenerative diseases (Alzheimer's disease, Parkinson disease, multiple sclerosis). The specific role of IL-1alpha in the development of neuropathic pain has not been previously established. The authors studied the mRNA expression and protein level of IL-1alpha (and other cytokines IL-1beta, IL-6, IL-10) in the spinal cord and dorsal root ganglia in rat model of neuropathic pain. Furthermore, they examed functional involvement of an IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) in nociceptive transmission in this model.

The main founding of the paper:
n rat model of neuropathic pain, IL-1alpha mRNA and protein were not detected in the spinal cord, but IL-1beta and IL-6 mRNAs were strongly ipsilaterally elevated. In the ipsilateral DRG, IL-1alpha, IL-6, and IL-10 mRNA levels were increased earlier then IL-1beta (Fig.1). Western blot analysis revealed both the presence of IL-1alpha proteins (45 and 31 kDa) in the DRG and the down-regulation of these proteins after injury (Fig.2). Intrathecal administration of IL-1alpha (50-500 ng) in naive rats did not influence nociceptive transmission, but IL-1beta (50-500 ng) induced hyperalgesia. In rat model of neuropathic pain, an IL-1alpha or IL-1 receptor antagonist dose-dependently attenuated symptoms of neuropathic pain; however, no effect of IL-1beta was observed (Fig.3). In sum, at the beginning of the development of neuropathic pain authors observed a high abundance of IL-1alpha in the DRG. Together with the antiallodynic and antihyperalgesic effects observed after IL-1alpha administration, this finding indicates an important antinociceptive role for IL-1alpha in the counteracting nociceptive stimulus induced by injury during development of neuropathic pain symptoms.

Implication for therapeutic strategy
The results presented by authors for the first time demonstrated that IL-1alpha is important for pain modulation on the DRG level. IL-1alpha elicits antinociceptive activity, and this difference in the behavioral effects of IL-1alpha and IL-1beta (which is pronociceptive) may be involved in the development of neuropathic pain symptoms, like allodynia and hyperalgesia. Significantly increased IL-1alpha gene transcription in the DRG may compensate for the lower level of IL-1alpha protein that is released to antagonize injury-induced nociceptive stimulation. It is interesting that IL-1alpha and IL-1beta act on the same receptor to differentially influence nociceptive transmission and the neuropathic pain response. Furthermore, the modulation of these interleukins' activities in the spinal cord and DRG may prove to be an interesting target for effective therapeutic strategy for the treatment of chronic pain.

References:

1. Gustafsson et al. Biochem Biophys Res Commun 2002; 297:492-7.
2. Obreja et al. FASEB J 2002;16:1497-503.
3. Opree et al. J Neurosci 2000;20:6289-93.
4. Relton et al. Brain Res Bull 1992;29:243-6.
5. Sung et al. Brain Res 2004;1015:145-53. 6. Sweitzer et al. Neuroscience 2001;103:529-39.

Curriculum Vitae:

Joanna Mika was born in Kraków, Poland. She graduated in 1995 the Jagiellonian University, after which she started work under supervision of Prof. Barbara Przewlocka in the Institute of Pharmacology, Polish Academy of Sciences in Kraków and in 1999 she presented Ph.D. dissertation "The role of opioid systems in neuropathic pain". She was also a holder of the few scholarships at the Nijmegen University (the Netherlands), David de Wied foundation; the Rudolf Magnus Institute for Neurosciences, Utrecht (the Netherlands) and the Leopold Kronenberg Bank Foundation; the Philipps University in Marburg (Germany). Since 2000 till 2003 she had postdoctoral position at the Philipps University in Marburg. Since 01.01.2004 she is working in the Department of Pain Pharmacology, Polish Academy of Sciences in Kraków.

Her main research interests: role of endogenous opioid peptides in physiology and pathology of the CNS; pharmacological and biochemical analysis of opioid effects in acute and chronic pain; effects of drugs on opioid gene expression; neurobiology and neuroimmunology of pain; role of interleukins and complement system in neurodegeneration.

Very strong upregulation of IL-1alpha in comparison with IL-1beta gene expression in dorsal root ganglia 3 and 7 days after injury - quantitative RT-PCR (ANOVA, *p<0.05; ***p<0.001 versus. contralateral sides).

(A) Presence of IL-1alpha (45 and 31kDa) protein in the dorsal root ganglia (DRG) and lack of this protein in the rat spinal cord (SC) - western blot. (B) Densitometric analysis reveal decrease of IL-1alpha (45kDa) protein in the DRG 3 and 7 days after injury. (ANOVA, ***p<0.001 vs. intact; +p<0.05; +++p<0.001 vs. contralateral sides).

Antiallodynic effect of rat IL-1alpha, but not IL-1beta (50, 125, 500ng) measured on ipsilateral paw in von Frey test 7 days after injury and 24h after ILs i.t. administration (ANOVA, *p<0.05; ***p<0.001 versus control).

Corresponding Address:
Ph.D. Joanna Mika12 Smetna Street
31343 Kraków
Poland