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

Fani Pantouli, Travis W. Grim, Cullen L. Schmid, Agnes Acevedo-Canabal, Nicole M. Kennedy, Thomas D. Bannister, Laura M. Bohn

Preprint posted on October 16, 2020 https://www.biorxiv.org/content/10.1101/2020.10.16.341776v1

Article now published in Neuropharmacology at http://dx.doi.org/10.1016/j.neuropharm.2020.108439

A novel analgesic drug as an alternative to morphine

Selected by Nándor Lipták

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?

 

  1. 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.

 

Posted on: 26th November 2020 , updated on: 25th January 2021

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

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Author's response

Laura M. Bohn shared

Q1: 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?

Answer: It is not known as this has not been measured. However, we showed that MORs’ levels were not changed as a results of the same 6-day treatment with 48 mg/kg SR-17018 (Grim et al. 2020).

 

Q2: 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?

Answer: Lower temps to prevent more than necessary nociception (jumping) and because once a C57BL6 mouse jumps, it usually jumps again, regardless of the nociception (learns the test). We look for the first sign that the mouse has recognized the source of nociception- and tries to remove its paw from contact (front or back paw). We also think is important to study how mice respond to the test in the absence of drug and use that response as a guide as mice will vary based on background and strain

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