-Endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis

Abstract

Objective: Intra-articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of b-endorphin (END), Met-enkephalin (ENK), and m and d opioid receptors (ORs) within synovium of patients with joint trauma (JT), osteoarthritis (OA) and rheumatoid arthritis (RA) were examined. Methods: Synovial samples were subjected to double immunohistochemical analysis of opioid peptides with immune cell markers, and of ORs with the neuronal markers calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH). Results: END and ENK were expressed by macrophage-like (CD68 + ) and fibroblast-like (CD68 2 ) cells within synovial lining layers of all disorders. In the sublining layers, END and ENK were mostly expressed by granulocytes in patients with JT, and by macrophages/monocytes, lymphocytes and plasma cells in those with OA and RA. Overall, END-and ENK-immunoreactive (IR) cells were more abundant in patients with RA than in those with OA and JT. ORs were found on nerve fibres and immune cells in all patients. OR-IR nerve fibres were significantly more abundant in patients with RA than in those with OA and JT. mORs and dORs were coexpressed with CGRP but not with TH. Conclusions: Parallel to the severity of inflammation, END and ENK in immune cells and their receptors on sensory nerve terminals are more abundant in patients with RA than in those with JT and OA. These findings are consistent with the notion that, with prolonged and enhanced inflammation, the immune and peripheral nervous systems upregulate sensory nerves expressing ORs and their ligands to counterbalance pain and inflammation.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Opioid peptides were detected in human subcutaneous and synovial cells, mast cells, granulocytes, lymphocytes, and macrophages. The prevailing peptides are END and Met-enkephalin, but dynorphin and endomorphins were also found Likar et al, 2004Likar et al, , 2007Heurich et al, 2007;Mousa et al, 2007b;Rittner et al, 2007a;Straub et al, 2008). In patients undergoing knee surgery, blockade of intra-articular opioid receptors by the local administration of naloxone resulted in significantly increased postoperative pain .…”

“…Peripheral mechanisms of opioid analgesia have gained recognition in the clinical setting. Opioid receptors were demonstrated on peripheral terminals of sensory nerves in human synovia Mousa et al, 2007b), dermal and epidermal nerve fibers (Ständer et al, 2002), and in dental pulp (Jaber et al, 2003). Analgesia after local (topical) opioid administration has been amply demonstrated in patients with various types of acute (e.g., orthopedic, dental, abdominal, urological, and eye surgery) and chronic pain (e.g., rheumatoid and osteoarthritis, oral mucositis, complex regional pain syndrome) (Azad et al, 2000;Dionne et al, 2001;Stein et al, 2003;Faktorovich and Basbaum, 2010).…”

“…Opioid receptor expression in sympathetic postganglionic neurons was also suggested. However, neither opioid receptor mRNA nor protein has been detected in such neurons (Coggeshall et al, 1997;Wenk and Honda, 1999;Stä nder et al, 2002;Mousa et al, 2007b). Moreover, whereas the C-fiber neurotoxin capsaicin decreased opioid receptor numbers in the DRG and abolished peripheral opioid antinociception (Barthó et al, 1990;Zhang et al, 1998a;Zhou et al, 1998), FIG. 1.…”

“…In peripheral tissues subpopulations of opioid peptidecontaining cells include granulocytes, monocytes/macrophages and lymphocytes (Przewłocki et al, 1992;Mousa et al, 2001Mousa et al, , 2007bRittner et al, 2001Rittner et al, , 2007aLabuz et al, 2006Labuz et al, , 2010Verma-Gandhu et al, 2006;Zöllner et al, 2008). Most notably, regulatory T cells (a population suppressing inflammatory responses) were shown to express the PENK gene (McHugh et al, 2002;Zelenika et al, 2002).…”

Clinical concentrations of morphine are cytotoxic on proliferating human fibroblasts in vitro

“…In the late 1980s, several studies showed that not only do opioids activate receptors in the brain and spinal cord but also activate receptors on peripheral sensory neurons. 1,2 Since then, different opioid pathways outside the central nervous system have been described, and new techniques such as intra-articular injections (local infiltration analgesia) and topical wound application have been introduced into clinical practice. [3][4][5] Many studies have focussed on NSAIDs as potential causes for non-union after fracture repair, 6 but, in a retrospective study, systemic opioids were also implicated in these complications.…”