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

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.

Ferroptosis inhibitor ferrostatin-1 attenuates morphine tolerance development in male rats by inhibiting dorsal root ganglion neuronal ferroptosis

“…Morphine exposure not only reduced the activities of antioxidants in target cells but also facilitated the production of free radicals, including ROS or reactive nitrogen species [ 47 ]. Avcı and Taşkıran [ 18 ] reported that morphine administration in single-dose and repeated doses decreased TAS levels and increased TOS levels in the DRG. This could indicate that morphine use inhibited the antioxidant system, potentially contributing to tolerance development.…”

“…The group size was determined by calculating power analysis. Furthermore, each experimental group in previous studies within this field consisted of six rats [ 18 ]. The animals were acclimated to the laboratory circumstances before the experiments took place.…”

“…For the experimental trials, fresh preparations of ferrostatin-1 (obtained from the Sigma-Aldrich Co.) dissolved in dimethyl sulfoxide (DMSO) and morphine sulfate (sourced from Sivas Cumhuriyet University Hospital in Turkey) dissolved in a saline solution were prepared. Before the analgesia tests, morphine (5 mg/kg) [ 18 ] and ferrostatin-1 (1 mg/kg) were given subcutaneously (s.c.) and i.p. respectively.…”

“…respectively. While using different routes of administration can introduce a difference in pharmacokinetics, measures were taken to ensure that the chosen routes and doses for each drug were well-established and in line with previous studies [ 18 , 19 ], to facilitate a meaningful comparison. A pilot study was conducted to determine the appropriate dose of ferrostatin-1.…”

Metformin prevents morphine-induced apoptosis in rats with diabetic neuropathy: a possible mechanism for attenuating morphine tolerance

“…DRG tissue samples of animals in cold phosphatebuffered saline solution (pH 7.4) were homogenized using a mechanical homogenizer (Analytik Jena speedmill plus, Jena, Germany). It was centrifuged at 4000 rpm for 10 minutes at a temperature of 4°C (Avci et al 2020). After obtaining the supernatants, they were stored at -80°C until biochemical analysis.…”