Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain

Brain Behav Immun. 2019 Nov;82:93-105. doi: 10.1016/j.bbi.2019.07.036. Epub 2019 Jul 31.


Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.

Keywords: Chronic pain; Conditioned place preference; Perispinal injection; Thermal hyperalgesia; Tumor necrosis factor-alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / pharmacology
  • Animals
  • Brain / metabolism
  • Chronic Pain / metabolism
  • Conditioning, Psychological
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hyperalgesia / metabolism
  • Injections, Intramuscular / methods
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Pain Perception / drug effects*
  • Pain Threshold / drug effects
  • Peripheral Nerve Injuries / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / metabolism
  • Tumor Necrosis Factor Inhibitors / administration & dosage
  • Tumor Necrosis Factor Inhibitors / pharmacology
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Analgesics
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha