A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

Wei Lei, Rakesh H. Vekariya, Subramaniam Ananthan, John M. Streicher

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)146-160
Number of pages15
JournalJournal of Pain
Issue number1-2
StatePublished - Jan 1 2020


  • HIV neuropathy
  • Mu opioid receptor
  • chemotherapy-induced neuropathy
  • delta opioid receptor
  • dependence
  • neuroinflammation
  • tolerance

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine


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