Peripheral Administration of Morphine Attenuates Postincisional Pain by Regulating Macrophage Polarization through COX-2-Dependent Pathway

Abstract

BackgroundMacrophage infiltration to inflammatory sites promotes wound repair and may be involved in pain hypersensitivity after surgical incision. We recently reported that the development of hyperalgesia during chronic inflammation is regulated by macrophage polarity, often referred to as proinflammatory (M1) or anti-inflammatory (M2) macrophages. Although opioids such as morphine are known to alter the inflammatory milieu of incisional wounds through interactions with immunocytes, the macrophage-mediated effects of morphine on the development of postincisional pain have not been well investigated. In this study, we examined how morphine alters pain hypersensitivity through phenotypic shifts in local macrophages during the course of incision-induced inflammation.ResultsLocal administration of morphine in the early phase, but not in the late phase alleviated mechanical hyperalgesia, and this effect was reversed by clodronate-induced peripheral depletion of local macrophages. At the morphine-injected incisional sites, the number of pro-inflammatory F4/80+iNOS+M1 macrophages was decreased during the course of pain development whereas increased infiltration of wound healing F4/80+CD206+M2 macrophages was observed during the early phase. Morphine increased the gene expression of endogenous opioid, proenkephalin, and decreased the pronociceptive cytokine, interleukin-1β. Heme oxygenase (HO)-1 promotes the differentiation of macrophages to the M2 phenotype. An inhibitor of HO-1, tin protoporphyrin reversed morphine-induced analgesic effects and the changes in macrophage phenotype. However, local expression levels of HO-1 were not altered by morphine. Conversely, cyclooxygenase (COX)-2, primarily produced from peripheral macrophages in acute inflammation states, was up-regulated in the early phase at morphine-injected sites. In addition, the analgesic effects and a phenotype switching of infiltrated macrophages by morphine was reversed by local administration of a COX inhibitor, indomethacin.ConclusionsLocal administration of morphine alleviated the development of postincisional pain, possibly by altering macrophage polarity at the incisional sites. A morphine-induced shift in macrophage phenotype may be mediated by a COX-2-dependent mechanism. Therefore, μ-opioid receptor signaling in macrophages may be a potential therapeutic target during the early phase of postincisional pain development.

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

“…Hence, strategies predominately based on dampening the proinflammatory properties of macrophages might be insufficient to inhibit pain. This is supported by a modest decrease or no changes in hypersensitivity after general depletion of macrophages in models of neuropathic, inflammatory, and postoperative pain (24)(25)(26)(27)(28).…”

“…Even though both exogenous and endogenous opioids activate the same opioid receptors, it is possible that these ligands initiate different downstream mechanisms to interact with various pain modality-dependent ion channels or intracellular pathways (36,53), and further studies are required. Interestingly, other studies found that M2 macrophages polarized by morphine or peroxisome proliferator-activated receptor-γ agonist reduced mechanical but not heat hypersensitivity in models of inflammatory and postoperative pain (28,54). Additionally, IL-4-knockout mice displayed enhanced, acute mechanical but unaltered heat sensitivity (55), although the reasons for these differences were not provided.…”

Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides

“…Though somewhat unexpected, the findings regarding M0 and M1 cells are in line with earlier studies suggesting a limited role of macrophages in the generation of pain. Hence, a general depletion of macrophages often resulted either in moderate elevations or no changes in the nociceptive thresholds in models of neuropathic, inflammatory, and postoperative pain [ 15 – 17 , 64 , 65 ]. Furthermore, injection at the nerve or into a hind paw of non-polarized peritoneal or bone marrow-derived macrophages or of IFN-γ-stimulated macrophages did not induce pain in sham-operated animals and did not enhance hypersensitivity induced by neuropathy or paw incision [ 17 , 22 , 27 ].…”

“…Few studies reported attenuation of both mechanical and heat hypersensitivity by activation of macrophage PPAR-γ or toll-like receptor 4 in incisional and CFA-induced inflammatory pain models [ 22 , 25 ]. Several other reports, however, found that a phenotypic shift to M2 in response to a PPAR-γ agonist or morphine did not improve heat, but attenuated mechanical hypersensitivity following hind paw incision or inflammation induced by carrageenan or CFA [ 23 , 24 , 65 ]. While the reasons for the differences among these studies and the mechanisms underlying the role of immune cells in the modulation of different pain modalities remain to be elucidated [ 67 ], our findings add to those which suggest that promoting an M2 phenotype might be particularly beneficial in improving mechanical hypersensitivity.…”

Heme oxygenase-1 inducer and carbon monoxide–releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice

“…Previous studies have shown that HO-1 signaling promotes macrophage/microglia polarization toward M2. 14 , 17 , 18 Although HO-1 induction has been reported to decrease microglial activation in neuropathic pain models, the association between HO-1 signaling and microglial polarization is unknown. 19 , 20 , 32 …”