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

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

Joshua Havelin  1 , Ian Imbert  1 , Jennifer Cormier  1 , Joshua Allen  1 , Frank Porreca  2 , Tamara King  3
Affiliations

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

Joshua Havelin et al. J Pain. 2016 Mar.

Abstract

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.

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Figures

Figure 1
Figure 1. Knee joint movement-induced FOS expression observed selectively in 4.8 mg MIA treated rats
A) Representative images depicting FOS expression in each of the treatment groups. Spinal map from The Rat Brain in Stereotaxic Coordinates, Fourth Edition, Paxinos and Watson. B) Movement of the knee joint (2 min, 1 movement/sec) produced a robust increase in FOS expressing cells within the spinal cord dorsal horn in rats treated with intra-articular injection of 4.8 mg MIA, but not 3.0 mg MIA or saline into the knee joint 14 days earlier. C) Movement of the knee joint increased FOS expression within the superficial dorsal horn (Laminae I&II). D) Knee joint movement increased FOS expression within the deep dorsal horn (Laminae III-V). Graphs represent Mean ± SEM, counts represent 6-8 sections across 3-4 rats per group.
Figure 2
Figure 2. RVM Lidocaine blocks MIA-induced ongoing pain
A) Diagram illustrating verification of bilateral cannulation of the RVM. Map from The Rat Brain in Stereotaxic Coordinates, Fourth Edition, Paxinos and Watson, 1998. Hits (dark colored circles) and misses (light colored circles) are illustrated. All misses were added to the off-site groups. B) Pre- and post- conditioning time spent in the lidocaine paired chamber demonstrates that only 4.8 mg MIA treated rats with on-site RVM lidocaine injections demonstrated increased time spent in the lidocaine paired chamber, *p<0.05 vs pre-lidocaine. C) Difference scores verify that RVM lidocaine produced preference selectively in rats treated with 4.8 mg MIA. No preference was observed in saline or 3.0 mg MIA treated rats, *p<0.05 vs off-site controls. Off-site injections failed to produce CPP. Graphs represent Mean ± SEM, n=6-16.
Figure 3
Figure 3. Systemic duloxetine blocks MIA-induced weight asymmetry and ongoing pain
A) Intra-articular MIA (4.8 mg/60 μl) produced weight asymmetry within 14 days of administration. Systemic duloxetine (30 mg/kg, i.p.) blocked MIA-induced weight asymmetry. Systemic saline failed to block the MIA-induced weight asymmetry. *p<0.05 vs Pre-MIA, #p<0.05 vs D14 (pre-duloxetine), n=9-19. B) Pre- and post-conditioning time spent in the intra-articular lidocaine paired chamber demonstrates that 4.8 mg MIA treated rats that received systemic saline 30 min prior to intra-articular lidocaine, increased time spent in the lidocaine paired chamber, *p<0.05 vs pre-conditioning. Systemic duloxetine (30 mg/kg, i.p.) blocked post-conditioning increase in the intra-articular lidocaine paired chamber. Rats treated with intra-articular saline failed to demonstrate increased time spent in the lidocaine-paired chamber irrespective of systemic (i.p.) saline or duloxetine treatment. n= 9 (intra-articular saline) and 17-19 (intra-articular MIA). C) Difference scores demonstrate that intra-articular lidocaine produced CPP in MIA (4.8 mg) treated rats that had been treated with saline (i.p.) 30 min prior to intra-articular lidocaine. Duloxetine (30 mg/kg, i.p.) blocked intra-articular lidocaine-induced CPP. *p<0.05 vs saline/saline controls. All graphs are mean ± SEM.
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