title: Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.
abstract: Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Pilat
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Piotrowska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rojewska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jurga
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ślusarczyk
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Basta-Kaim
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland. Electronic address: joamika@if-pan.krakow.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002047:Buprenorphine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004357:Drug Synergism; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; C118370:interleukin-18 binding protein; D002047:Buprenorphine; D009020:Morphine
keywords: IL-18; IL-18BP; IL-18R; Neuropathic pain; Opioid treatment