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

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Conflict of interest statement

Competing Interests

The authors declare no competing interests.

Figures

Fig. 1.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on nociceptive sensation in normal rats. Left panels show the time course for latency to respond to radiant heat applied to the plantar skin on the right foot (ipsilateral to the dorsal root ganglion stimulation placement [A]) and left foot (C), and to noxious mechanical stimulation (modified von Frey, right foot [E], left foot [G]). Dorsal root ganglion stimulation or spinal cord stimulation electrodes were implanted immediately after the baseline behavioral tests at day 0. Dorsal root ganglion stimulation or spinal cord stimulation was given 30 min and behavioral responses were monitored for another 30 min. Right panels (B, D, F, H) show the average of the area under the curve calculated for each rat for the time period during and 30 min after the dorsal root ganglion stimulation or spinal cord stimulation, normalized to the baseline just before stimulation. Results are means ± SD. Here and in other time sequence data, each timepoint was compared to the 0 time baseline for that group and to the same timepoint for the control group, and a planned comparison design was used for these post hoc tests. *P < 0.05, **P < 0.01 by the Tukey test after one-way ANOVA; 1, P < 0.05 and 2, P < 0.01 compared to data immediately before dorsal root ganglion stimulation; a, P < 0.05 and b, P < 0.01 compared to sham treatment group by the Dunnett test after two-way repeated measures ANOVA with Greenhouse–Geisser correction; n, number of animals.

Fig. 2.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on rats with tibial nerve injury. Dorsal root ganglion stimulation or spinal cord stimulation electrodes were implanted immediately after the baseline (day 0) behavioral determinations. Animals were assigned only to one treatment group and electrodes were only inserted at the sites at which active treatment was given. Tibial nerve injury surgeries were performed 7 days after the electrode implantation. Time course for effects are shown in the left panels, and area under curve analysis for group comparisons are shown in the right panels, for sensitivity to noxious mechanical stimuli (pin [A, B]), threshold mechanical stimuli (von Frey [C, D]), cold (E, F), and brush (G, H). The Sham treatment group consisted of animals with a spinal cord stimulation electrode or dorsal root ganglion stimulation electrode (at L4 and L5) that were inserted but not activated. Results in A, E, and G are median ± interquartile range. Results in B, C, D, F, and H are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by the Tukey test after one-way ANOVA. 1, P < 0.05; 2, P < 0.01; and 3, P < 0.001 compared to data immediately before dorsal root ganglion stimulation; a, P < 0.05; b, P < 0.01; and c, P < 0.001 compared to Sham treatment group by the Dunnett test after two-way repeated measures ANOVA with Greenhouse–Geisser correction; n, number of animals.

Fig. 3.

Effects of dorsal root ganglion stimulation on male and female rats with tibial nerve injury. Dorsal root ganglion stimulation or spinal cord stimulation electrodes were implanted immediately after the baseline (day 0) behavioral determinations. Time course for effects are shown in the left panels, and area under curve analysis for group comparisons are shown in the right panels, for sensitivity to noxious mechanical stimuli (pin [A, B]), threshold mechanical stimuli (von Frey [C, D]), cold (E, F), and brush (G, H). Results in A, E, and G are median ± interquartile range. Results in B, C, D, F and H are mean ± SD. 1, P < 0.05; 2, P < 0.01; and 3, P < 0.001 compared to data immediately before dorsal root ganglion stimulation by the Dunnett test after two-way repeated measures ANOVA with Greenhouse–Geisser correction; n, number of animals.

Fig. 4.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on incapacitance test in rats with tibial nerve injury. Time course for effects on weight-bearing asymmetry are shown in A, and area under curve analysis for group comparisons are shown in B. Results are mean ± SD. **P < 0.01; ***P < 0.001 by the Tukey test after one-way ANOVA. 1, P < 0.05; 2, P < 0.01; and 3, P < 0.001 compared to data immediately before dorsal root ganglion stimulation; a, P < 0.05; b, P < 0.01; and c, P < 0.001 compared to Sham treatment group by the Dunnett test after two-way repeated measures ANOVA with Greenhouse–Geisser correction; n, number of animals.

Fig. 5.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on Conditioned Place Preference test in rats with tibial nerve injury. (A) Sequence of events. (B) Preference at baseline (Pretest) and after treatment or Sham treatment, and the treatment effect normalized to the Pretest baseline. Results are mean ± SD. * P < 0.05; ** P < 0.01 by the paired t test (B) and the Tukey test after one-way ANOVA (C). n, number of animals.

Fig. 6.

Effects of dorsal root ganglion stimulation on Conditioned Place Preference test in rats, showing preference at baseline (Pretest) and after treatment (A), and the treatment effect normalized to the Pretest baseline (B). The time course for onset of analgesia by gabapentin (100 mg/kg intraperitoneally) in tibial nerve injury animals is shown for pin (C) and von Frey test (D; n = 8). Gabapentin was injected 60 min before conditioning those rats with dorsal root ganglion stimulation and Sham dorsal root ganglion stimulation. Results in A are median ± interquartile range. All other results are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001 by the paired t test (A), the Tukey test after one-way ANOVA (B), and the Dunnett test after one-way repeated-measures ANOVA (C). n, number of animals.

Fig. 7.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on rats with monosodium iodoacetate-induced osteoarthritis pain. The time course for effects are shown in the left panels, and area under curve analysis for group comparisons are shown in the right panels, for plantar sensitivity to noxious mechanical stimuli (pin [A, B]), plantar sensitivity to threshold mechanical stimuli (von Frey [C, D]), and weight-bearing asymmetry (E, F). Solid arrows in A, C, and Erepresent intraarticular injection of monosodium iodoacetate and stimulation electrodes implantation. Results in A are median ± interquartile range. Results in other panels are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by the Tukey test after one-way ANOVA. 1, P < 0.05; 2, P < 0.01; and 3, P < 0.001 compared to data immediately before dorsal root ganglion stimulation; a, P < 0.05, b, P < 0.01, and c, P < 0.001 compared to Sham treatment group by the Dunnett test after two-way repeated measures ANOVA with Greenhouse–Geisser correction; n, number of animals.

Fig. 8.

Effects of dorsal root ganglion stimulation/spinal cord stimulation on rats with monosodium iodoacetate-induced osteoarthritis pain, showing responses ipsilateral and contralateral to the monosodium iodoacetate injection for the threshold for withdrawal from knee compression using a pressure application measurement device (A). Also shown are the scored response to knee bending (B), and group comparisons for area under curve. Results are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 by the Tukey test after one-way ANOVA; 2, P < 0.01 by the paired t test; n, number of animals.

Fig. 9.

Effects of dorsal root ganglion stimulation and spinal cord stimulation on Conditioned Place Preference test in rats with monosodium iodoacetate-induced osteoarthritis pain, showing preference at baseline (Pretest) and after treatment (A), and the treatment effect normalized to the Pretest baseline (B). Results are mean ± SD. *P < 0.05, **P < 0.01 by the paired t test (A) and the Tukey test after one-way ANOVA (B). n, number of animals.