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The Journal of Neuroscience, April 19, 2006, 26(16):4350-4358; doi:10.1523/JNEUROSCI.4349-05.2006

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Behavioral/Systems/Cognitive
Peripheral Antinociceptive Effects of Exogenous and Immune Cell-Derived Endomorphins in Prolonged Inflammatory Pain

Dominika Labuz,¹ Stephan Berger,¹ Shaaban A. Mousa,¹ Christian Zöllner,¹ Heike L. Rittner,¹ Mohammed A. Shaqura,¹ Toni Segovia-Silvestre,¹ Barbara Przewlocka,² Christoph Stein,¹ and Halina Machelska¹

¹Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, D-12200 Berlin, Germany, and ²Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland

Correspondence should be addressed to Dr. Halina Machelska, Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. Email: halina.machelska{at}charite.de

Endomorphins (EMs) are endogenous selective µ-opioid receptor agonists. Their role in inflammatory pain has not been fully elucidated. Here we examine peripheral antinociception elicited by exogenously applied EM-1 and EM-2 and the contribution of EM-containing leukocytes to stress- and corticotropin-releasing factor (CRF)-induced antinociception. To this end, we applied behavioral (paw pressure) testing, radioligand binding, immunohistochemistry, and flow cytometry in rats with unilateral hindpaw inflammation induced with Freund’s adjuvant. EMs injected directly into both hindpaws produced antinociception exclusively in inflamed paws. This was blocked by locally applied µ-receptor-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂) but not -receptor-selective (nor-binaltorphimine) antagonists. -Receptor antagonists (naltrindole and N,N-diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. Antibodies against -endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. Both EMs displaced binding of [³H]-[D-Ala²,N-Me-Phe⁴,Gly⁵-ol]enkephalin to µ-receptors in dorsal root ganglia (DRG). Using [³H]-naltrindole or [¹²⁵I]-[D-Pen2,5]-enkephalin, no detectable -binding was found in DRG of inflamed hindlimbs. Numerous -endorphin-containing and fewer EM-1- and EM-2-containing leukocytes were detected in subcutaneous tissue of inflamed paws. Leukocyte-depleting serum decreased the number of immigrating opioid-containing immune cells and attenuated swim stress- and CRF-induced antinociception in inflamed paws. Both forms of antinociception were strongly attenuated by anti--endorphin and to a lesser degree by anti-EM-1 and anti-EM-2 antibodies injected into inflamed paws. Together, exogenously applied and immune cell-derived EMs alleviate prolonged inflammatory pain through selective activation of peripheral opioid receptors. Exogenous EM-2 in addition to µ-receptors also activates peripheral -receptors, which does not involve actions via other opioid peptides.

Key words: endomorphin; immune cells; leukocytes; antinociception; inflammation; pain

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Received Oct. 12, 2005; revised Feb. 27, 2006; accepted Feb. 28, 2006.

Correspondence should be addressed to Dr. Halina Machelska, Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. Email: halina.machelska{at}charite.de

This article has been cited by other articles:

				H. L. Rittner, A. Brack, and C. Stein Pain and the immune system Br. J. Anaesth., July 1, 2008; 101(1): 40 - 44. [Abstract] [Full Text] [PDF]

				F. A. White, H. Jung, and R. J. Miller Chemokines and the pathophysiology of neuropathic pain PNAS, December 18, 2007; 104(51): 20151 - 20158. [Abstract] [Full Text] [PDF]

				V. Fernandez-Duenas, O. Pol, P. Garcia-Nogales, L. Hernandez, E. Planas, and M. M. Puig Tolerance to the Antinociceptive and Antiexudative Effects of Morphine in a Murine Model of Peripheral Inflammation J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 360 - 368. [Abstract] [Full Text] [PDF]

				S. A Mousa, R. H Straub, M. Schafer, and C. Stein {beta}-Endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis Ann Rheum Dis, July 1, 2007; 66(7): 871 - 879. [Abstract] [Full Text] [PDF]

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