Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

Abstract

Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.

Meta‐Analysis for Correlating Structure of Bioactive Peptides in Foods of Animal Origin with Regard to Effect and Stability

“…This is supported by the anti-inflammatory peptides, which inhibit neutrophil aggregation and regulate expression of adhesion molecules (such asselectins and integrins) on the surface of leukocytes (Camussi, Tetta, & Baglioni, 1990;Zouki, Ouellet, & Filep, 2000). Opioid peptides bind to opioid receptors present in both the central and peripheral nervous systems; they are involved in the regulations of pain (Labuz, Celik, Zimmer, & Machelska, 2016;Madden, Akil, Patrick, & Barchas, 1977), a person's mood through their effect on dopamine release (Spanagel, Herz, & Shippenberg, 1990), drinking and feeding (Duraffourd et al, 2012;Kaneko, Yoshikawa, & Ohinata, 2012;Reid, 1985), sleep (Wang & Teichtahl, 2007), body temperature (Clark, 1979), stress responses (Madden et al, 1977;Shavit, Lewis, Terman, Gale, & Liebeskind, 1984), sexual maturation by modulating secretion of luteinizing hormone (Blank, Panerai, & Friesen, 1979), taste preferences (Drenowski, Krahn, Demitrack, Nairn, & Gosnell, 1992), and in the development of the nervous system (Zagon & McLaughlin, 1991). They are usually referred to as opioid receptor ligands that exhibit morphine-like effects, which can be inhibited by naloxone (Meisel, 1998;Park & Nam, 2015;Silva & Malcata, 2005;Wada & Lönnerdal, 2014).…”

Usefulness of knockout mice to clarify the role of the opioid system in chronic pain

“…In chronic pain models, β‐endorphin knockout mice showed normal nociceptive sensitization to thermal and mechanical stimuli in inflammatory (Gendron et al, ; Walwyn et al, ) and peripheral neuropathy models (Petraschka et al, ; Niikura et al, ,b; Labuz et al, ). However, these mice retained sensitivity to MOP agonists during neuropathic pain, whereas wild‐type mice experienced the normal tolerance to MOP stimulation.…”

“…Few studies have explored the consequences of Penk ablation in chronic pain (Labuz et al, ; Walwyn et al, ). Heat and mechanical sensitization was normal in models of inflammatory and neuropathic pain (Celik et al, ; Walwyn et al, ).…”

“…Acute inflammatory pain was increased in the late phase of the formalin test (Wang et al, ). In contrast, mechanical hypersensitivity after chronic sciatic nerve constriction (Labuz et al, ) and mechanical and heat hypersensitivity after spinal nerve ligation or PSNL were decreased (Wang et al, ; Xu et al, ). In agreement, the latter study showed a reduction in KOP phosphorylation in the spinal cord accompanied by reduced astrocytosis in Pdyn knockouts after PSNL, suggesting a pronociceptive role of Pdyn gene products (Xu et al, ).…”

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

“…through the arachidonic acid cascade, they also play a role in mediating endogenous peripheral analgesia, as reflected by the increased expression of opioid receptors on the peripheral terminals of sensory neurons and heightened local production of opioid peptides at the site of inflammation (10,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This suggests an integral role of the immune system in mediating analgesia in response to noxious stimuli.…”