Afferent drive elicits ongoing pain in a model of advanced osteoarthritis

Abstract

Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (ie, ongoing pain) that is generally resistant to nonsteroidal antiinflammatory drugs. Injection of monosodium iodoacetate (MIA) into the intraarticular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intraarticular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a transient receptor potential V1 channel (TRPV1) antagonist, effectively blocked thermal hypersensitivity, but failed to block high-dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intraarticular HC030031, a TRPA1 antagonist, failed to block high-dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intraarticular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.

Figure 1

A) Toluidine blue staining of the joint was performed 2 weeks post injection. MIA produced a decrease in the amount of cartilage lining the medial femoro-tibial joint compared to saline treated joints. B) Radiographic images of joints demonstrate that intra-articular injection of MIA results in an apparent dose-dependent joint degeneration. High-resolution radiographs of the knee joints demonstrate smooth femoral and tibial bones in naïve rats (control) whereas rough edges of the tibia and femur are observed in joints that had been treated with 1, 3, or 4.8 mg MIA. In addition, diminished space between the tibia and femur is apparent by 15 days post-MIA, particularly in the joints treated with 3 and 4.8 mg MIA.

Figure 2

A) Intra-articular (i.a.) injection of 1, 3 and 4.8 mg of MIA all induced a shift in weight bearing. B) Intra-articular (i.a.) administration of lidocaine (200 µl, 4% w/v) reversed the MIA-induced (4.8 mg) shift in weight bearing within 20 min at 14 days following MIA administration. This effect dissipated within 120 min. * indicates p<0.05 vs post-MIA, n=7. C) Rats treated with the 4.8 mg dose of MIA increased time spent in the lidocaine paired chamber at 14 days following MIA treatment. Rats treated with the lower doses of MIA or saline did not show preference for the lidocaine or the saline treated chambers. * indicates p<0.05 compared to pre-conditioning time spent in chamber (n=7 saline, n=12, 12, and 7 for MIA at 1, 3 and 4.8 mg, respectively). D) Difference scores (test time-preconditioning time) confirmed that rats treated with 4.8 mg of MIA increased time spent in the lidocaine paired chamber. * indicates p<0.05 compared to saline. E) Treatment with intra-articular lidocaine in the ipsilateral, but not contralateral joint produced conditioned place preference in rats treated with 4.8 mg of MIA. F) Difference scores confirmed that ipsilateral, but not contralateral intra-articular lidocaine leads to an increase in time spent in the lidocaine paired chamber.

Figure 3

A) Systemic administration of diclofenac (30 mg/kg, p.o.) reversed the MIA-induced (4.8 mg) shift in weight bearing, *p<.05 vs post-MIA, n=8. B) Systemic administration of diclofenac (30 mg/kg, p.o.) failed to block conditioned place preference to a chamber paired with intra-articular lidocaine 45 minutes post-diclofenac,. No pre-conditioning differences were observed in any treatment group. Intra-articular lidocaine failed to produce CPP in the saline (i.a.) treated rats. * indicates p < 0.05 compared to pre-conditioning time spent in chamber (n=6–8). C) Difference from baseline scores (test time-preconditioning (BL) time) confirmed that intra-articular lidocaine produced equivalent preference in MIA treated rats irrespective of diclofenac treatment. * indicates p<0.05 compared to saline.

Figure 4

A) Systemic administration of AMG9810 (30 mg/kg, i.p.) reversed MIA-induced thermal hyperalgesia observed at 14 days post-MIA injection (i.a.), *p<0.05 vs Pre-drug, n=8–10. B) Systemic administration of AMG9810 (30 mg/kg, i.p.) partially reversed the MIA-induced shift in weight bearing at the 3 mg, but not the 4.8 mg dose of MIA (n=8). C) Systemic administration of AMG9810 (30 mg/kg, i.p.) failed to block conditioned place preference to a chamber paired with intra-articular lidocaine 30 min post-AMG9810, **p<0.01 vs pre-conditioning, n=6. No pre-conditioning differences were observed in any treatment group. Intra-articular lidocaine failed to produce CPP in the saline (i.a.) treated rats. D) Difference from baseline scores (test time-preconditioning (BL) time) confirmed that intra-articular lidocaine produced equivalent preference in MIA treated rats irrespective of AMG9810 treatment, **p<0.01.

Figure 5

A) Mustard oil (1%, 100 µl) injected into the plantar surface of the hind paw induced paw lifting behavior that was attenuated by systemic administration of HC030031 (100 mg/kg, p.o.) 60 min prior to mustard oil injection, **p<.01 vs vehicle, n=6. B) Systemic administration of HC030031(100 mg/kg, p.o.) failed to reverse the MIA-induced shift in weight bearing (n=7 and 8 for 3 and 4.8 mg MIA, respectively). C) Systemic administration of HC 030031 (100 mg/kg, p.o.) failed to block conditioned place preference to a chamber paired with intra-articular lidocaine 60 min post-HC030031. * indicates p<0.05 vs pre-conditioining (n=9–12). D) Difference from baseline scores (test time-preconditioning (BL) time) confirmed that intra-articular lidocaine produced equivalent preference in MIA treated rats irrespective of HC030031 treatment. * indicates p<0.05 vs saline.

Figure 6

A) Mustard oil (1%, 100 µl) injected into the plantar surface of the hind paw induced paw lifting behavior that was attenuated by a intraplantar injection of HC030031 (200 µg/100 µl) given 5 min prior to mustard oil injection. * indicates p<0.05 vs vehicle, n=6. B) Intra-articular HC030031 (200 µg/100 µl) failed to reverse the MIA-induced shift in weight bearing (n=8). C) Intra-articular HC030031 (200 µg/100 µl) failed to produce conditioned place preference (n=12).