Dorsal Root Ganglion Stimulation Alleviates Pain-related Behaviors in Rats with Nerve Injury and Osteoarthritis.

Abstract

Dorsal root ganglion field stimulation is an analgesic neuromodulation approach in use clinically, but its mechanism is unknown as there is no validated animal model for this purpose. The authors hypothesized that ganglion stimulation is effective in reducing pain-like behaviors in preclinical chronic pain models. The authors provided ganglion stimulation or spinal cord stimulation to rats with traumatic neuropathy (tibial nerve injury), or osteoarthritis induced by intraarticular knee monosodium iodoacetate, or without injury (naïve). Analgesia was evaluated by testing a battery of pain-related reflexive, functional, and affective behaviors. In rats with nerve injury, multilevel L4 and L5 ganglion stimulation decreased hypersensitivity to noxious mechanical stimulation more (area under curve, -1,447 ± 423 min × % response; n = 12) than single level ganglion stimulation at L4 ([-960 ± 251 min × % response; n = 8; P = 0.012] vs. L4 and L5), and L5 ([-676 ± 295 min × % response; n = 8; P < 0.0001] vs. L4 and L5). Spontaneous pain-like behavior, evaluated by conditioned place preference, responded to single L4 (Pretest [-93 ± 65 s] vs. Test [87 ± 82 s]; P = 0.002; n = 9), L5 (Pretest [-57 ± 36 s] vs. Test [137 ± 73 s]; P = 0.001; n = 8), and multilevel L4 and L5 (Pretest: -81 ± 68 s vs. Test: 90 ± 76 s; P = 0.003; n = 8) ganglion stimulation. In rats with osteoarthritis, multilevel L3 and L4 ganglion stimulation reduced sensitivity to knee motion more (-156 ± 28 min × points; n = 8) than L3 ([-94 ± 19 min × points in knee bend test; n = 7; P = 0.002] vs. L3 and L4) or L4 ([-71 ± 22 min × points; n = 7; P < 0.0001] vs. L3 and L4). Conditioned place preference during osteoarthritis revealed analgesic effectiveness for ganglion stimulation when delivered at L3 (Pretest [-78 ± 77 s] vs. Test [68 ± 136 s]; P = 0.048; n = 9), L4 (Pretest [-96 ± 51 s] vs. Test [73 ± 111 s]; P = 0.004; n = 9), and L3 and L4 (Pretest [-69 ± 52 s; n = 7] vs. Test [55 ± 140 s]; P = 0.022; n = 7). Dorsal root ganglion stimulation is effective in neuropathic and osteoarthritic preclinical rat pain models with peripheral pathologic origins, demonstrating effectiveness of ganglion stimulation in a placebo-free setting and justifying this model as a suitable platform for mechanistic studies.