Highlights
- •A Mu-Delta Opioid agonist SRI-22141 displays enhanced efficacy in neuropathic pain.
- •SRI-22141 displays greatly reduced tolerance and dependence versus morphine.
- •SRI-22141 also has an anti-inflammatory effect in chemotherapy-induced neuropathy.
- •Efficacy and anti-inflammation effects are mediated by the Delta Opioid Receptor.
Abstract
Numerous studies have demonstrated a physiological interaction between the mu opioid
receptor (MOR) and delta opioid receptor (DOR) systems. A few studies have shown that
dual MOR-DOR agonists could be beneficial, with reduced tolerance and addiction liability,
but are nearly untested in chronic pain models, particularly neuropathic pain. In
this study, we tested the MOR-DOR agonist SRI-22141 in mice in the clinically relevant
models of HIV Neuropathy and Chemotherapy-Induced Peripheral Neuropathy (CIPN). SRI-22141
was more potent than morphine in the tail flick pain test and had equal or enhanced
efficacy versus morphine in both neuropathic pain models, with significantly reduced
tolerance. SRI-22141 also produced no jumping behavior during naloxone-precipitated
withdrawal in CIPN or naïve mice, suggesting that SRI-22141 produces little to no
dependence. SRI-22141 also reduced tumor necrosis factor-α and cyclooxygenase-2 in
CIPN in the spinal cord, suggesting an anti-inflammatory mechanism of action. The
DOR-selective antagonist naltrindole strongly reduced CIPN efficacy and anti-inflammatory
activity in the spinal cord, without affecting tail flick antinociception, suggesting
the importance of DOR activity in these models. Overall, these results provide compelling
evidence that MOR-DOR agonists could have strong efficacy with reduced side effects
and an anti-inflammatory mechanism in the treatment of neuropathic pain.
Perspective
This study demonstrates that a MOR-DOR dual agonist given chronically in chronic neuropathic
pain models has enhanced efficacy with strongly reduced tolerance and dependence,
with a further anti-inflammatory effect in the spinal cord. This suggests that MOR-DOR
dual agonists could be effective treatments for neuropathic pain with reduced side
effects.
Key words
Abbreviations:
AUC (area under the curve), βarr2 (βarrestin2), CIPN (Chemotherapy-Induced Peripheral Neuropathy), CT (cycle threshold), COX-2 (cyclooxygenase-2), GI (gastrointestinal), MOR DOR KOR (Mu, delta, and kappa opioid receptors), TNFα (tumor necrosis factor-α)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: June 12, 2019
Accepted:
May 29,
2019
Received in revised form:
May 14,
2019
Received:
March 25,
2019
Footnotes
Disclosures: Dr. Streicher and Dr. Ananthan report grants from the National Institutes of Health (R01DA008883 and R01DA038635), during the conduct of the study; a grant from Depomed, Inc, grant from Stealth Biotherapeutics, and an ownership stake in Teleport Pharmaceuticals, LLC, outside the submitted work. In addition, Dr. Ananthan has a patent US 9,163,030 issued. Institutional funds from the University of Arizona (to J.M.S.) also supported this work. The authors have no further conflicts of interest to declare.
Identification
Copyright
© 2019 by United States Association for the Study of Pain, Inc.
