E LPS further lowers nociceptive thresholds. Application ofSauer et al. Molecular
E LPS further lowers nociceptive thresholds. Application ofSauer et al. Molecular Pain 2014, 10:10 http://www.molecularpain.com/content/10/1/Page 10 ofa TLR4-inhibitor in CFA inflammation further worsens baseline thermal and mechanical hyperalgesia.Peripheral opioid mediated analgesiaDifferent subpopulations of immune cells contribute to peripheral opioid-mediated antinociception. purchase GSK343 neutrophils play an important role in the first phase because depletion of neutrophils in CFA inflammation or skin incision increases thermal hyperalgesia but not mechanical hyperalgesia [13-15]. Neutrophils are activated via chemokines or formyl peptides to secrete opioid peptides. Mobilization of neutrophils using GM-CSF treatment in CFA inflammation has no effect on mechanical hyperalgesia [31] and, on the contrary, even increases pain in neuropathic pain models [32]. Opioid-producing T cells are important soldiers in the battle against pain in different models including inflammatory pain [18,33] neuropathic pain [19] and visceral pain [20]. In CFA-induced arthritis antigen-specific activated, but not resting CD4+ T lymphocytes are responsible for the spontaneous relief of inflammation-induced pain following Ag challenge [18,33]. Analgesia was observed by transferring effector CD4+ T lymphocytes with Th1 or Th2 phenotype, suggesting that antinociceptive activity is a fundamental property of effector CD4+ T lymphocytes irrespective of their effector functions [18]. Similarly, in immunocompromised mice with chronic constriction neuropathy transfer of T-cells reverses neuropathic pain at later stages [19,34]. In later phases of CFA inflammation monocytes/macrophages are the major opioid-containing cells. Reduction (but not depletion) of monocytes/macrophages via clodoranate containing liposomes by 30 decreases opioid dependent swim stress-induced antinociception and has no effect on baseline hyperalgesia [23]. A higher PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28045099 selective depletion of monocytes/macrophages was not achieved. Therefore, we used the unselective immune depletion by CTX in this study. This treatment further worsened inflammatory mechanical hyperalgesia. Local application of -opioid receptor antagonists decreased thermal nociceptive thresholds. In accordance, mechanical nociceptive thresholds were lowered by intraplantar injection of naloxone or anti–END antibodies [29]. No PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27385778 change of nociceptive thresholds was observed in contralateral paws in this study or rats without inflammation in previous studies [28] arguing against a general proalgesic property of CTX. Peripheral opioid-dependent analgesia is mostly shortterm possibly because aminopeptidase N or neutral endopeptidases produced by leukocytes or peripheral nerves rapidly degrade opioid peptides [35]. Peripheral opioidmediated analgesia lasts only shortly (around 10 min) in early inflammation when mostly neutrophils are triggered by chemokines or formyl peptides [13,14]. We now show that monocyte-based peripheral opioid-mediated analgesiavia LPS lasts longer up to 30 min at 4 d after i.pl. CFA injection. Since both macrophages and neutrophils express activated aminopeptidase N or neutral endopeptidases we postulate that the longer duration of antinociception is due to a more sustained release. In accordance, we found that 15, 60 and 120 min stimulation of monocytes in vitro lead to significant opioid peptide release. Our results are in contrast with a recent publication in mice with CFA inflammation [36]. In this model tissue injury pr.