Presence of a reduced opioid response in interleukin‐6 knock out mice

Bianchi, Mauro; Maggi, Roberto; Pimpinelli, Federica; Rubino, Tiziana; Parolaro, Daniela; Poli, Valeria; Ciliberto, Gennaro; Panerai, Alberto E.; Sacerdote, Paola

doi:10.1046/j.1460-9568.1999.00563.x

Cited by 56 publications

(41 citation statements)

References 55 publications

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“…In IL-6 knockout mice, reduced morphine analgesia and early development of morphine tolerance were observed (Bianchi et al, 1999). IL-6 knockout mice used in that study showed increases in b-endorphin levels and decreases in m-opioid receptor densities in certain brain regions compared to that of wildtype mice (Bianchi et al, 1999). This suggests that an altered opioid system in these animals could be responsible for differences in morphine actions compared to that of wildtype animals.…”

Section: Opioid and Cytokine Interactionsmentioning

confidence: 77%

“…Alternatively, the role of IL-6 in modulating morphine actions is unclear. In IL-6 knockout mice, reduced morphine analgesia and early development of morphine tolerance were observed (Bianchi et al, 1999). IL-6 knockout mice used in that study showed increases in b-endorphin levels and decreases in m-opioid receptor densities in certain brain regions compared to that of wildtype mice (Bianchi et al, 1999).…”

Section: Opioid and Cytokine Interactionsmentioning

confidence: 83%

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Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Raghavendra

Tanga

DeLeo

2003

Neuropsychopharmacol

233

175

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The activation of glial cells and enhanced proinflammatory cytokine expression at the spinal cord has been implicated in the development of morphine tolerance, and morphine withdrawal-induced hyperalgesia. The present study investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced glial activation and enhanced proinflammatory cytokine levels at the lumbar spinal cord. Moreover, glial activation and enhanced proinflammatory cytokine levels exhibited a temporal correlation with the expression of morphine tolerance and hyperalgesia. Consistently, propentofylline attenuated the development of hyperalgesia and the expression of spinal analgesic tolerance to morphine. The administration of propentofylline during the induction of morphine tolerance also attenuated glial activation and proinflammatory cytokines at the L5 lumbar spinal cord. These results further support the hypothesis that spinal glia and proinflammatory cytokines contribute to the mechanisms of morphine tolerance and associated abnormal pain sensitivity.

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Section: Opioid and Cytokine Interactionsmentioning

confidence: 77%

Section: Opioid and Cytokine Interactionsmentioning

confidence: 83%

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Raghavendra

Tanga

DeLeo

2003

Neuropsychopharmacol

233

175

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“…Bianchi et al (1999) revealed that the analgesic effect was reduced in IL-6 knockout mice, and IL-6 deficient mice produced tolerance to analgesic drugs. Our data also indicate a correlation between IL-6 genotype and pain in NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

Correlation analysis between an IL-6 genetic polymorphism and non-small cell lung cancer prognosis

Zhao

Tian

2016

Genet. Mol. Res.

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ABSTRACT. Interleukin-6 (IL-6) is a multifunctional cytokine that is involved in tumor cell proliferation, apoptosis, and differentiation. The purpose of this study was to evaluate the impact of the single nucleotide polymorphism (SNP) -174G/C in IL-6 on the prognosis and pain tolerance of non-small cell lung cancer (NSCLC) patients. DNA was extracted from the peripheral blood of 434 patients with NSCLC, which was diagnosed by cytology or histology. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the IL-6 -174G/C genotypes and their correlation with survival was analyzed. The IL-6 -174G/C genotypes were high IL-6 production type (G carriers -GG or GC genotypes) and low IL-6 production type (CC genotype). The correlation between the IL-6 SNP and pain level/analgesic use was also analyzed. Survival analysis showed that patients carrying the G allele (CG/GG) had a shorter survival time than patients with the CC genotype. The -174G/C SNP is in the promoter region of the IL-6 gene and may be associated with changes in gene transcription and serum cytokine levels. Presence of the IL-6 -174G/C SNP is significantly correlated with morphine equivalent daily dose. Patients with the CC genotype needed a higher opioid dose than patients with the GG or GC genotypes. In conclusion, we found that the IL-6 -174G/C SNP is closely related to survival, analgesic use and pain tolerance in NSCLC patients. However, it is necessary to further validate the results with a larger patient cohort and elucidate the mechanisms of this SNP. Link to retraction noticed R E T R A C T I O N

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“…There are reports demonstrating that the cytokine IL-6 acts at the site of inflammation on resident and circulating immune cells to cause the release of endogenous opioids, which subsequently activate peripheral opioid receptors to produce analgesia (12,13). Whether the antinociceptive activity of AG490 is mediated by release of endogenous …”

Section: Discussionmentioning

confidence: 99%

“…The antinociceptive activity of AG490 was evaluated using this model. Previous studies have shown that IL-6 reduces hyperalgesia by increasing spinal µ-opioid receptor during chronic inflammation (10,11) and also releases opioid peptides from immune cells (12,13). Therefore, whether the antinociceptive activity of AG490 involves the opioid system at peripheral site was also investigated.…”

Section: Introductionmentioning

confidence: 99%

Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain

et al. 2015

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Abstract. Interleukin 6 (IL-6) has a critical role in pain mechanisms. IL-6 signals through the Janus-activated kinases 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway. The contribution of JAK2 signaling in inflammation-induced hyperalgesia has not been addressed previously. The role of this pathway was investigated using the JAK2 inhibitor, AG490, in a rat model of inflammatory pain. Unilateral hind paw inflammatory pain was induced in male Sprague-Dawley rats by intraplantar (i.pl.) injection of 3.5% ʎ-carrageenan. Inflamed rats received an i.pl. injection of either 3.5% of dimethylsulfoxide or AG490 (1-10 µg). The antinociceptive effects of AG490 were assessed by 2 pain behavioral assays 4 h later: The thermal and mechanical hyperalgesia tests. AG490 (1-10 µg) significantly attenuated ʎ-carrageenan-induced thermal hyperalgesia in a dose-dependent manner. AG490 also reduced mechanical hyperalgesia. Co-administration of opioid receptor antagonist naloxone (10 µg) and AG490 (10 µg) did not reverse AG490-produced antinociceptive activity, suggesting that the µ-opioid receptor is not responsible for the anti-hyperalgesic effects of AG490. Therefore, we suggest that AG490 produces these effects by blocking JAK2 signaling. In conclusion, JAK2 inhibitors may represent a novel class of non-narcotic drugs to treat inflammatory pain.

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Presence of a reduced opioid response in interleukin‐6 knock out mice

Cited by 56 publications

References 55 publications

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Correlation analysis between an IL-6 genetic polymorphism and non-small cell lung cancer prognosis

Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain

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