Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice. IF 4.211

Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed. Structure-activity studies were performed on opioid agonist/NK1 receptor antagonist hybrid peptides by modification of the C-terminal amide substituents. All compounds were evaluated for their affinity and in vitro activity at the mu opioid (MOP) and delta opioid (DOP) receptors, and for their affinity and antagonist activity at the NK1 receptor. On the basis of their in vitro profiles, the analgesic properties of two new bifunctional hybrids were evaluated in naive and CCI-mice, representing models for acute and neuropathic pain, respectively. The compounds were administered to the spinal cord by lumbar puncture. In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.

Original languageEnglish
Pages (from-to)2315-2324
Number of pages10
JournalACS Chemical Neuroscience
Issue number10
Early online date26 Jul 2017
Publication statusPublished - 18 Oct 2017


  • Analgesics, Opioid/pharmacology
  • Analgesics/pharmacology
  • Animals
  • Chronic Disease
  • Constriction
  • Ligands
  • Mice
  • Neuralgia/drug therapy
  • Receptors, Neurokinin-1/drug effects
  • Receptors, Opioid, delta/drug effects
  • Receptors, Opioid, mu/agonists
  • Spinal Cord Injuries/drug therapy
  • Spinal Cord/drug effects


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