Intrathecal neuropeptide Y reduces behavioral and molecular markers of inflammatory or neuropathic pain

Pain. 2008 Jul 15;137(2):352-365. doi: 10.1016/j.pain.2007.09.016. Epub 2007 Oct 31.


Our previous work indicates that the intrathecal administration of neuropeptide Y (NPY) acts at its cognate receptors to reduce behavioral signs of nociception in several models of inflammatory pain, including the formalin test. The present study extends these findings to a rat model of peripheral neuropathic pain, and then evaluates the hypothesis that NPY inhibits inflammation- and nerve injury-induced activation of spinal nociceptive transmission. Here we show that NPY dose-dependently reduced behavioral signs of mechanical and cold hypersensitivity in the spared nerve injury (SNI) model. Intrathecal administration of either a Y1 (BIBO3304) or a Y2 (BIIE0246) receptor antagonist dose-dependently reversed the anti-allodynic actions of NPY. To monitor the effects of NPY on the stimulus-induced activation of spinal nociresponsive neurons, we quantified protein expression of the immediate-early gene c-fos in lamina I-VI of the L4-L5 dorsal horn, with special attention to the mediolateral pattern of Fos immunohistochemical staining after SNI. Either tactile stimulation of the hindpaw ipsilateral to nerve injury, or intraplantar injection of noxious formalin, increased the number of Fos-like immunoreactive profiles. Tactile stimulation evoked a mediolateral pattern of Fos expression corresponding to the innervation territory of the uninjured (sural) nerve. We found that intrathecal NPY reduced both formalin- and SNI-induced Fos expression. NPY inhibition of SNI-induced Fos expression was localized to the sural (uninjured) innervation territory, and could be blocked by intrathecal BIBO3304 and BIIE0246. We conclude that NPY acts at spinal Y1 and Y2 receptors to reduce spinal neuron activity and behavioral signs of inflammatory or neuropathic pain.

Publication types

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

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Cell Count
  • Dose-Response Relationship, Drug
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Injections, Spinal
  • Male
  • Neuropeptide Y / pharmacology*
  • Neuropeptide Y / therapeutic use
  • Pain Measurement
  • Peripheral Nervous System Diseases / drug therapy*
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / physiopathology
  • Physical Stimulation
  • Posterior Horn Cells / cytology
  • Posterior Horn Cells / drug effects*
  • Posterior Horn Cells / metabolism
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors
  • Receptors, Neuropeptide / metabolism
  • Receptors, Neuropeptide Y / antagonists & inhibitors
  • Receptors, Neuropeptide Y / metabolism
  • Sciatic Neuropathy / complications*
  • Sciatic Neuropathy / physiopathology


  • Analgesics
  • Anti-Inflammatory Agents
  • Neuropeptide Y
  • Npy1r protein, rat
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Receptors, Neuropeptide Y
  • neuropeptide Y2 receptor