Analysis of the distribution of spinal NOP receptors in a chronic pain model using NOP-eGFP knock-in mice

Br J Pharmacol. 2018 Jul;175(13):2662-2675. doi: 10.1111/bph.14225. Epub 2018 May 6.


Background and purpose: The nociceptin/orphanin FQ opioid peptide (NOP) receptor system plays a significant role in the regulation of pain. This system functions differently in the spinal cord and brain. The mechanism by which the NOP receptor agonists regulate pain transmission in these regions is not clearly understood. Here, we investigate the peripheral and spinal NOP receptor distribution and antinociceptive effects of intrathecal nociceptin/orphanin FQ (N/OFQ) in chronic neuropathic pain.

Experimental approach: We used immunohistochemistry to determine changes in NOP receptor distribution triggered by spinal nerve ligation (SNL) using NOP-eGFP knock-in mice. Antinociceptive effects of intrathecal N/OFQ on SNL-mediated allodynia and heat/cold hyperalgesia were assessed in wild-type mice.

Key results: NOP-eGFP immunoreactivity was decreased by SNL in the spinal laminae I and II outer, regions that mediate noxious heat stimuli. In contrast, immunoreactivity of NOP-eGFP was unchanged in the ventral border of lamina II inner, which is an important region for the development of allodynia. NOP-eGFP expression was also decreased in a large number of primary afferents in the L4 dorsal root ganglion (DRG) of SNL mice. However, SNL mice showed increased sensitivity, compared to sham animals to the effects of i.t administered N/OFQ with respect to mechanical as well as thermal stimuli.

Conclusions and implications: Our findings suggest that the spinal NOP receptor system attenuates injury-induced hyperalgesia by direct inhibition of the projection neurons in the spinal cord that send nociceptive signals to the brain and not by inhibiting presynaptic terminals of DRG neurons in the superficial lamina.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / pharmacology
  • Animals
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Disease Models, Animal*
  • Female
  • Gene Knock-In Techniques
  • Green Fluorescent Proteins / antagonists & inhibitors
  • Green Fluorescent Proteins / metabolism
  • Injections, Spinal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nociceptin Receptor
  • Opioid Peptides / antagonists & inhibitors*
  • Opioid Peptides / metabolism
  • Receptors, Opioid / analysis*
  • Receptors, Opioid / metabolism
  • Spinal Cord / chemistry*
  • Spinal Cord / drug effects


  • Analgesics, Opioid
  • Opioid Peptides
  • Receptors, Opioid
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Nociceptin Receptor
  • Oprl1 protein, mouse