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. 2020 Dec 17;50(8):2048-2058.
doi: 10.3906/sag-2005-256.

Anakinra, an interleukin-1 receptor antagonist, increases the morphine analgesic effect and decreases morphine tolerance development by modulating oxidative stress and endoplasmic reticulum stress in rats

Onur Avcı  1 , Ahmet Şevki Taşkıran  2
Affiliations

Anakinra, an interleukin-1 receptor antagonist, increases the morphine analgesic effect and decreases morphine tolerance development by modulating oxidative stress and endoplasmic reticulum stress in rats

Onur Avcı et al. Turk J Med Sci. .

Abstract

Background/aim: Recent studies have shown that inflammation plays a role in morphine analgesia and tolerance development. Anakinra is a competitive inhibitor of IL-1 receptors and an antiinflammatory protein regulating IL-1β’s biological activity by avoiding signal transduction. In this study, we aimed to examine the effects of anakinra on morphine analgesia and tolerance.

Materials and methods: In this study, 36 Wistar Albino (230–250 g) male rats were used. Animals were divided into 6 groups: saline (S), 100 mg/kg anakinra (A), 5mg/kg morphine (M), M+A, morphine tolerance (MT), and MT+A. The resulting analgesic effect was measured with hot plate and tail-flick analgesia tests. After the analgesia tests, the dorsal root ganglions (DRG) tissues were removed. Oxidative stress parameters [total antioxidant status (TAS), total oxidant status (TOS)], endoplasmic reticulum (ER) stress, and apoptosis proteins [E74-like factor 2 (elF-2α), activating transcription factor 4 (ATF-4), C/EBP homologous protein (CHOP), caspase-3, and bcl-2-associated X protein (bax)] were measured in DRG tissues.

Results: Anakinra showed an antinociceptive effect when given alone (P < 0.001). In addition, anakinra increased the analgesic effect of morphine (P < 0.05 to P < 0.001), and also decreased the tolerance to morphine at a significant level (P < 0.05 to P < 0.001). Moreover, it decreased oxidative stress and ER-stress when given as a single-dose morphine and tolerance induction (P < 0.01 to P < 0.001). Furthermore, anakinra decreased apoptosis proteins after tolerance development (P < 0.001).

Conclusion: Anakinra has antinociceptive properties, and it increases the analgesic effect of morphine and also prevents tolerance development. These effects probably occur by the modulation of oxidative stress and ER-stress pathways.

Keywords: Anakinra; endoplasmic reticulum stress; morphine analgesia; morphine tolerance; oxidative stress.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1
Figure 1
Experimental design of the study.
Figure 2
Figure 2
Effect of anakinra on nociception and morphine analgesia. (a) shows the effect of anakinra on nociception and morphine analgesia in the tail flick test; (b) shows the effect of anakinra on nociception and morphine analgesia in the hot plate test. Values are expressed as the means ± SEM of % MPE (n = 6). ***P < 0.001 compared to saline group. #P < 0.05, ##P < 0.01, and ###P < 0.001, compared to the morphine group.
Figure 3
Figure 3
Effect of anakinra on morphine tolerance development. (a) shows the effect of anakinra on morphine tolerance development in the tail flick test; (b) shows the effect of anakinra on morphine tolerance development in the hot plate test. Values are expressed as the means ± SEM of % MPE (n = 6). *P < 0.05 and ***P < 0.001, compared to the saline group. ++P < 0.01 and +++P < 0.001, compared to morphine group. #P < 0.05, ##P < 0.01, and ###P < 0.001, compared to the morphine tolerance group.
Figure 4
Figure 4
Effect of anakinra on antioxidant and oxidant parameters (TAS and TOS levels) in morphine analgesia and tolerance in DRG (a) shows the effect of anakinra on TAS levels in morphine analgesia and tolerance in DRG; (b) shows the effect of anakinra on TOS levels in morphine analgesia and tolerance in DRG. Values are expressed as the means ± SEM of % MPE (n = 6). ***P < 0.001, compared to the saline group. +++P < 0.001, compared to the morphine group. ###P < 0.001, compared to the morphine tolerance group.
Figure 5
Figure 5
Effect of anakinra on ER-stress proteins (elF-2α, ATF-4, and CHOP levels) in morphine analgesia and tolerance in DRG (a) shows the effect of anakinra on elF-2α levels in morphine analgesia and tolerance in DRG; (b) shows the effect of anakinra on ATF-4 levels in morphine analgesia and tolerance in DRG; (c) shows the effect of anakinra on CHOP levels in morphine analgesia and tolerance in DRG. Values are expressed as the means ± SEM of % MPE (n = 6). **P < 0.01 and ***P < 0.001, compared to the saline group. +++P < 0.001, compared to the morphine group. ###P < 0.001, compared to the morphine tolerance group.
Figure 6
Figure 6
Effect of anakinra on apoptosis (caspase-3 and bax levels) in morphine analgesia and tolerance in DRG. (a) effect of anakinra on caspase-3 levels in morphine analgesia and tolerance in DRG; (b) shows the effect of anakinra on bax levels in morphine analgesia and tolerance in DRG. Values are expressed as the means ± SEM of % MPE (n = 6). ***P < 0.001, compared to the saline group. +++P < 0.001, compared to the morphine group. ###P < 0.001, compared to the morphine tolerance group.
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