T lymphocytes containing β-endorphin ameliorate mechanical hypersensitivity following nerve injury.
Neuropathic pain is a debilitating consequence of nerve injuries and is frequently resistant to classical therapies. T lymphocytes mediate adaptive immune responses and have been suggested to generate neuropathic pain. In contrast, in this study we investigated T cells as a source of opioidergic analgesic β-endorphin for the control of augmented tactile sensitivity following neuropathy. We employed in vivo nociceptive (von Frey) testing, flow cytometry and immunofluorescence in wild-type and mice with severe combined immunodeficiency (SCID) subjected to a chronic constriction injury of the sciatic nerve. In wild-type mice, T lymphocytes constituted approximately 11% of all immune cells infiltrating the injury site, and they expressed β-endorphin and receptors for corticotropin-releasing factor (CRF), an agent releasing opioids from leukocytes. CRF applied at the nerve injury site fully reversed neuropathy-induced mechanical hypersensitivity in wild-type animals. In SCID mice, T cells expressing β-endorphin and CRF receptors were absent at the damaged nerve. Consequently, these animals had substantially reduced CRF-mediated antinociception. Importantly, the decreased antinociception was fully restored by transfer of wild-type mice-derived T lymphocytes in SCID mice. The re-established CRF antinociception could be reversed by co-injection of an antibody against β-endorphin or an opioid receptor antagonist with limited access to the central nervous system. We propose that, in response to CRF stimulation, T lymphocytes accumulating at the injured nerves utilize β-endorphin for activation of local neuronal opioid receptors to reduce neuropathy-induced mechanical hypersensitivity. Our findings reveal β-endorphin-containing T cells as a crucial component of beneficial adaptive immune responses associated with painful peripheral nerve injuries.
Labuz
Dominika
D
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Krahmerstrasse 6, Berlin, Germany.
Schreiter
Anja
A
Schmidt
Yvonne
Y
Brack
Alexander
A
Machelska
Halina
H
D000700:Analgesics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009292:Narcotic Antagonists; D009437:Neuralgia / Q000276:immunology* / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000523:psychology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001615:beta-Endorphin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000700:Analgesics; D009292:Narcotic Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; D001615:beta-Endorphin