Tolerance to the antinociceptive and hypothermic effects of morphine is mediated by multiple isoforms of c-Jun N-terminal kinase

Abstract

The abuse and overdose of opioid drugs are growing public health problems, globally. While progress has been made towards understanding the mechanisms governing tolerance to opioids, the exact cellular machinery involved remains unclear. However, there is growing evidence to suggest that c-Jun N-terminal Kinases (JNKs) play a major role in mu opioid receptor regulation and morphine tolerance. In this study, we aimed to determine the potential roles of different JNK isoforms in development of tolerance to the anti-nociceptive and hypothermic effects of morphine. We used the hotplate and tail-flick tests for thermal pain to measure tolerance to the anti-nociceptive effects of once daily sub-cutaneous injections with 10 mg/kg morphine. Body temperature was also measured to determine tolerance to the hypothermic effects of morphine. Tolerance to morphine was assessed in wild-type mice and compared to single knockout (KO) mice each lacking of the JNK isoforms (JNK1, JNK2, or JNK3). We found that loss of each individual JNK isoform causes impairment in tolerance for the anti-nociceptive and hypothermic effects of daily morphine. However, disruption of JNK2 seems to have the most profound effect on morphine tolerance. These results demonstrate a clear role for JNK signaling pathways in morphine tolerance. This compliments previous studies suggesting that the JNK2 isoform is required for morphine tolerance, but additionally presents novel data suggesting that additional JNK isoforms also contribute to this process.

Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

“…Quercetin, a PIK3cg inhibitor, previously has shown to reduce thermal hyperalgesia in diabetic mice (Anjaneyulu and Chopra, 2003). The thalidomide and SP600125 results presented here are supported by previous studies using rodent models of opioid tolerance (Babbini and Davis, 1972;Chai et al, 2011;Khan et al, 2017;Yuill et al, 2016). Thalidomide is also involved with the inhibition of TNF-α, a mediator of the inflammatory immune response (Klausner et al, 1996), which is important to note, as ligation of the spinal nerve creates a local inflammatory response contributing to the development of tolerance and/or mechanical hyperalgesia.…”

Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain

“…Since previous published work from our laboratory has demonstrated that JNK signaling is required for morphine tolerance, we examined whether JNK signaling was required for morphine-induced cross-tolerance to JWH-133. 29 , 30 This experiment was done by examining the efficacy of JWH-133 (1 mg/kg) anti-nociception in the formalin model using mice that received either five days of repeated morphine alone (10 mg/kg), mice that received daily pre-treatment with SP6 (3 mg/kg) prior to morphine (10 mg/kg), and mice receiving daily vehicle injections. Pre-treatment with SP6 was given 60 min before injection of morphine.…”

<p>The Interaction Between Spinal PDGFRβ and μ Opioid Receptor in the Activation of Microglia in Morphine-Tolerant Rats</p>

“…8 Previous studies showed that platelet-derived growth factor receptor β submit (PDGFRβ) could be phosphorylated during chronic morphine treatment. 9 Although PDGF-BB could activate microglia through PDGFRβ and produce tactile allodynia, 10 whether there is a link between activations of microglia and PDGFRβ in the mechanism of morphine tolerance is still unknown.…”