Pain mechanismInterleukin-1 beta contributes to the upregulation of kappa opioid receptor mrna in dorsal root ganglia in response to peripheral inflammation
Section snippets
Animals
Animal protocols were approved by the Landesamt für Arbeitsschutz, Gesundheitsschutz und Technische Sicherheit, Berlin, Germany, and are in accordance with the International Association for the Study of Pain (Zimmermann 1983). The number of animals used was minimized, and animals did not suffer under the treatments described here. Inflammation was induced by injection of 0.15 ml of Freund’s complete adjuvant (FCA; Calbiochem, La Jolla, CA, USA) into the right hindpaw of male Wistar rats
Detection and quantification of KOR mRNA in DRG
Primers detected mRNA of the expected size in target tissue (DRG) as well as in reference tissue (midbrain) in the conventional PCR (Fig. 1A). Genomic DNA was not detectable in RT-negative samples. To further ensure specificity of amplification, PCR products were sequenced and were compared with the published sequence of KOR showing a homology of over 99% (data not shown). Using light cycler polymerase chain reaction (LC-PCR), KOR mRNA content in DRG of untreated control animals was quantified (
Discussion
We found that unilateral paw inflammation results in an upregulation of KOR mRNA in ipsilateral DRG after 12 h, followed by a significant increase in KOR-positive cells in DRG detected by immunohistochemistry after 24 h. The proinflammatory cytokine IL-1β mimics this effect via its receptor. Expression of IL-1β and IL-1ra was upregulated in the paw following local injection of FCA and IL-1β, respectively. Treatment with IL-1ra prevented KOR upregulation without changes in the peripheral
Conclusion
In summary, we have shown that KOR mRNA and protein in DRG are upregulated in response to peripheral inflammation. The proinflammatory cytokine IL-1β mediates this effect. These findings suggest a key role for IL-1β in KOR mRNA upregulation in response to painful inflammation.
Acknowledgments
This study was supported by the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe 100/2) and by the International Anesthesia Research Society. The authors wish to thank Dr. S. J. Watson, University of Michigan, Ann Arbor, MI, USA, and Dr. R. Elde, University of Minnesota, Minneapolis, MN, USA for generously providing the rabbit primary antibody for KOR as well as the KOR synthetic peptide as well as Ms. Susanne Kotré and Ms. Katharina Hopp, Berlin, for expert technical assistance.
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TNF-α, CXCL-1 and IL-1 β as activators of the opioid system involved in peripheral analgesic control in mice
2021, European Journal of PharmacologyCitation Excerpt :Following the release cascade of mediators in mice, our results showed that selective and non-selective opioid receptor antagonists also potentiated the hyperalgesia induced by IL-1β and reduced by bestatin. A study showed that a single intraplantar injection of IL-1β was able to enhance the axonal transport of opioid μ and κ receptors in the injected paw (Puehler et al., 2006). Another study found that the increase in receptors may be due to an increase in receptor synthesis and that IL-1β may stimulate the retrograde axonal transport of proinflammatory cytokines and nerve growth factor from inflamed tissue, which will alter opioid receptors’ gene expression in dorsal root ganglia neurons (Busch-Dienstfertig and Stein, 2010).
Immune cell-mediated opioid analgesia
2020, Immunology LettersCitation Excerpt :This effect is dependent on electrical neuronal activity and nerve growth factor-induced activation of p38 mitogen-activated protein kinase (MAPK) in peripheral inflamed tissue [19,66–69]. The upregulation and enhanced transport of kappa-receptors were mediated by interleukin [IL]-1β [70,71]. The CFA-induced inflammation also augmented the recruitment of intracellular delta-receptors to the membrane in DRG neurons, making the receptors accessible to agonists [72].
- 1
W.P. and H.L.R. contributed equally.