Elsevier

Neuroscience

Volume 141, Issue 2, 2006, Pages 989-998
Neuroscience

Pain mechanism
Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mrna in dorsal root ganglia in response to peripheral inflammation

https://doi.org/10.1016/j.neuroscience.2006.03.078Get rights and content

Abstract

During local painful inflammation, axonal transport of opioid receptors from dorsal root ganglia toward the periphery is increased, associated with a higher receptor density and enhanced efficacy of opioid analgesics at the injured site. To examine whether this increase is related to transcription, mRNA of the kappa opioid receptor in lumbar dorsal root ganglia was quantified by real time light cycler polymerase chain reaction. In dorsal root ganglia of naive rats, kappa opioid receptor mRNA expression was three-fold higher than previously shown for delta opioid receptor and two times lower than mu opioid receptor mRNA, respectively. After induction of unilateral paw inflammation by Freund’s complete adjuvant, kappa opioid receptor mRNA was significantly upregulated with a peak at 12 h in ipsilateral dorsal root ganglia. This effect could be mimicked by intraplantar injection of the proinflammatory cytokine interleukin-1 beta. Kappa opioid receptor mRNA upregulation lasted longer in interleukin-1 beta–treated rats compared with Freund’s complete adjuvant–treated rats. Furthermore, a significant increase in kappa opioid receptor positive neurons was detected by immunohistochemistry 24 h after local injection of Freund’s complete adjuvant or interleukin-1 beta. In Freund’s complete adjuvant–induced inflammation, kappa opioid receptor upregulation was blocked by treatment with interleukin-1 receptor antagonist without changing the leukocyte infiltration in the paw.

In conclusion, kappa opioid receptor mRNA and protein in dorsal root ganglia are upregulated in response to peripheral inflammation. This effect can be mimicked by a single local injection of interleukin-1 beta, and Freund’s complete adjuvant–induced upregulation in kappa opioid receptor mRNA and protein can be prevented by treatment with interleukin-1 receptor antagonist. These data suggest that the peripheral production of the proinflammatory cytokine interleukin-1 beta is a specific inducer of kappa opioid receptor expression in the dorsal root ganglia.

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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    W.P. and H.L.R. contributed equally.

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