title: Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain.
abstract: Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral mu-opioid receptors (micro-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of mu-receptors was significantly increased and G protein coupling of mu-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of mu-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance.
authors.affiliation: Klinik für Anaesthesiologie und operative Intensivmedizin, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. christian.zoellner@charite.de
authors.forename: Christian
authors.initials: C
authors.lastname: Zöllner
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Oliver
authors.initials: O
authors.lastname: Fischer
authors.forename: Heike L
authors.initials: HL
authors.lastname: Rittner
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaqura
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Waltraud
authors.initials: W
authors.lastname: Binder
authors.forename: Florian
authors.initials: F
authors.lastname: Urban
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology; D004361:Drug Tolerance; D005283:Fentanyl / Q000627:therapeutic use; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009475:Neurons, Afferent / Q000473:pathology; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism; D001615:beta-Endorphin / Q000502:physiology
chemical_list: D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001615:beta-Endorphin; D009020:Morphine; D003520:Cyclophosphamide; D005283:Fentanyl