Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine

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 alter...

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Published in:Molecular and cellular neuroscience 2016-03, Vol.71, p.114-124
Main Authors: Pilat, Dominika, Piotrowska, Anna, Rojewska, Ewelina, Jurga, Agnieszka, Ślusarczyk, Joanna, Makuch, Wioletta, Basta-Kaim, Agnieszka, Przewlocka, Barbara, Mika, Joanna
Format: Article
Language:English
Subjects:
Analgesics, Opioid - administration & dosage
Analgesics, Opioid - pharmacology
Analgesics, Opioid - therapeutic use
Animals
Astrocytes - drug effects
Astrocytes - metabolism
Buprenorphine - administration & dosage
Buprenorphine - pharmacology
Buprenorphine - therapeutic use
Cells, Cultured
Drug Synergism
IL-18
IL-18BP
IL-18R
Intercellular Signaling Peptides and Proteins - administration & dosage
Intercellular Signaling Peptides and Proteins - metabolism
Intercellular Signaling Peptides and Proteins - pharmacology
Interleukin-18 - genetics
Interleukin-18 - metabolism
Male
Morphine - administration & dosage
Morphine - pharmacology
Morphine - therapeutic use
Neuralgia - drug therapy
Neuralgia - metabolism
Neurons - drug effects
Neurons - metabolism
Neuropathic pain
Opioid treatment
Rats
Rats, Wistar
Receptors, Interleukin-18 - genetics
Receptors, Interleukin-18 - metabolism
Spinal Cord - cytology
Spinal Cord - metabolism
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Summary: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 100ng) 7 or 14days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5μg) 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. [Display omitted] •During neuropathic pain equilibrium between algesic (IL-18) and analgesic (IL-18BP) factors is disrupted.•LPS-enhance pro- IL-18 in microglia and anti-nociceptive IL-18BP in astroglia primary cultures•IL-18BP enhances morphine and buprenorphine analgesia in neuropathy.
ISSN:1044-7431
1095-9327
DOI:10.1016/j.mcn.2015.12.013