Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain

Background

Morphine exerts its effect on specific G-protein coupled opioid receptors: κ opioid receptors (KORs), μ opioid receptors (MORs), δ opioid receptors (DORs) and orphan receptor like receptor-1. All type of these receptors mediate analgesic actions, but MORs have a main role in morphine-induced analgesia. The analgesic effect of SR-17018, a MOR-selective agonist was similar to morphine in mice (Schmid et al. 2017). SR-17018 did not produce analgesic tolerance in the hot plate test, reversed tolerance to morphine and prevented morphine withdrawal (Grim et al. 2020), suggesting that SR-17018 could be a promising analgesic drug.

β-arrestin2 has a prominent role in the analgesia evoked by MOR agonists as a negative regulator of MOR signaling (Whistler & von Zastrow 1998; Zhang et al. 1998). The lack of β-arrestin2 resulted in the prolonged analgesic effect of morphine (Bohn et al. 1999; Bohn et al. 2000).

SR-17018 proved to be effective to induce analgesia in the hot-plate test in mice, but its efficiency in other pain-response tests has not been clarified so far. In this preprint, the potential analgesic effect of SR-17018 was characterized in detail by several behavior assays in mice.

  

Key findings

Tail-flick, hot-plate (heat-induced pain), formalin test (chemical-induced pain), Paclitaxel-induced neuropathic pain (von Frey test, mechanical) were used to evaluate the analgesic effect of SR-17018. For tolerance experiments, SR-17018 and oxycodone were administrated in vehicle for 6 days via osmotic minipumps or orally.

Chronic administration of SR-17018 evokes tolerance in the tail flick-test, although it did not induce tolerance in the hot-plate test (Grim et al. 2020)

There were no significant differences in tail-flick analgesic tolerance between oxycodone, morphine and SR-17018. Morphine tolerant mice showed tolerance to SR-17018 and SR-17018 tolerant mice showed tolerance to morphine.

Replacement with SR-17018 did not reverse tolerance to morphine, although morphine sensitivity was restored in the hot-plate test (Grim et al. 2020)

Analgesic tolerance in the formalin test

Acute SR-17018 effectively suppressed the response in the second phase following chronic vehicle or chronic SR-17018, proving it retains efficacy following chronic treatment.

Paclitaxel-induced neuropathy pain model

All mice have showed hyperalgesia by day 7. Compared with day 7, SR-17018 was effective at elevating thresholds on day 8 and after repeated dosing, while the effect of oxycodone was not significant on day 8 compared to day 7.

 

Why I liked this preprint

In clinical medicine, morphine is still considered to be the best analgesic drug for the alleviation of postoperative pain. SR-17018 might be a good alternative of morphine without the unwanted side effects (tolerance, dependence, withdrawal-induced depression).

 

 Questions for the authors

1. It is known that chronic morphine treatment changes the levels of endogenous opiates in different brain regions in rats, e.g. reduced dynorphin A level in both lobes of the pituitary gland, reduced Leu-encephalin levels in the hypothalamus (Nylander et al. 1995); and in mice, e.g. proenkephalin mRNA level was reduced in the nucleus accumbens and remained unchanged in the striatum, etc. (Turchan et al. 1997).Does SR-17018 also disturb the endogenous opiates’ system in mice in the aforementioned brain regions or in the spinal medulla?

 

2. In the description of the hot-plate test, only the withdrawing of the paw was mentioned as a sign of pain-response. In the original reports, licking of paws and jumping were the signs of pain-induced behavior in mice (Eddy & Leimbach 1953; Fernandes et al. 1977). Why did you modify the assessment of the hot-plate test and what were the benefits of the changes compared with the original method?

 

References

Bohn L.M., Gainetdinov R.R., Lin F.T., Lefkowitz R.J. & Caron M.G. (2000) mu-Opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720-3.

Bohn L.M., Lefkowitz R.J., Gainetdinov R.R., Peppel K., Caron M.G. & Lin F.T. (1999) Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286, 2495-8.

Eddy N.B. & Leimbach D. (1953) Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. Journal of Pharmacology and Experimental Therapeutics 107, 385-93.

Fernandes M., Kluwe S. & Coper H. (1977) Quantitative assessment of tolerance to and dependence on morphine in mice. Naunyn Schmiedebergs Arch Pharmacol 297, 53-60.

Grim T.W., Schmid C.L., Stahl E.L., Pantouli F., Ho J.H., Acevedo-Canabal A., Kennedy N.M., Cameron M.D., Bannister T.D. & Bohn L.M. (2020) A G protein signaling-biased agonist at the mu-opioid receptor reverses morphine tolerance while preventing morphine withdrawal. Neuropsychopharmacology 45, 416-25.

Nylander I., Vlaskovska M. & Terenius L. (1995) The effects of morphine treatment and morphine withdrawal on the dynorphin and enkephalin systems in Sprague-Dawley rats. Psychopharmacology (Berl) 118, 391-400.

Schmid C.L., Kennedy N.M., Ross N.C., Lovell K.M., Yue Z., Morgenweck J., Cameron M.D., Bannister T.D. & Bohn L.M. (2017) Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell 171, 1165-75 e13.

Turchan J., Lason W., Budziszewska B. & Przewlocka B. (1997) Effects of single and repeated morphine administration on the prodynorphin, proenkephalin and dopamine D2 receptor gene expression in the mouse brain. Neuropeptides 31, 24-8.

Whistler J.L. & von Zastrow M. (1998) Morphine-activated opioid receptors elude desensitization by beta-arrestin. Proceedings of the National Academy of Sciences of the United States of America 95, 9914-9.

Zhang J., Ferguson S.S., Barak L.S., Bodduluri S.R., Laporte S.A., Law P.Y. & Caron M.G. (1998) Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc Natl Acad Sci U S A 95, 7157-62.

 

doi: https://doi.org/10.1242/prelights.25904

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