Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis

J Pain. 2016 Mar;17(3):374-82. doi: 10.1016/j.jpain.2015.12.001. Epub 2015 Dec 13.


Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain and a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present study, palpation of the ipsilateral hind limb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced expression of the early oncogene, FOS, in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways using a microinjection of lidocaine within the rostral ventromedial medulla induced conditioned place preference selectively in rats treated with the high dose of MIA. Conditioned place preference to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, intraperitoneally at -30 minutes). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID-resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that might guide drug discovery for treatment of advanced OA pain without the need for joint replacement.

Perspective: Difficulty in managing advanced OA pain often results in joint replacement therapy in these patients. Improved understanding of mechanisms driving NSAID-resistant ongoing OA pain might facilitate development of alternatives to joint replacement therapy. Our findings suggest that central sensitization and neuropathic features contribute to NSAID-resistant ongoing OA joint pain.

Keywords: Advanced osteoarthritis; central sensitization; descending facilitation; duloxetine; neuropathic pain.

Publication types

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

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Arthralgia / drug therapy
  • Arthralgia / physiopathology*
  • Central Nervous System Sensitization / drug effects
  • Central Nervous System Sensitization / physiology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Duloxetine Hydrochloride / pharmacology
  • Hindlimb
  • Lidocaine / pharmacology
  • Male
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / physiopathology
  • Neuralgia / drug therapy
  • Neuralgia / physiopathology*
  • Osteoarthritis, Knee / drug therapy
  • Osteoarthritis, Knee / physiopathology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Spinal Cord / physiopathology


  • Analgesics
  • Proto-Oncogene Proteins c-fos
  • Duloxetine Hydrochloride
  • Lidocaine