Analgesic Tolerance Development during Repetitive Electric Stimulations Is Associated with Changes in the Expression of Activated Microglia in Rats with Osteoarthritis

Abstract

Electric stimulation is used for managing osteoarthritic (OA) pain; however, little is known about the development of analgesic tolerance during repeated stimulations and the relation of spinal microglia with OA pain. We investigated the changes in the analgesic effects of repeated electric stimulations and the relation between the development of analgesic tolerance and spinal microglial expression in rats with OA. To induce OA, monosodium iodoacetate was injected into the synovial space of the right knee joint of the rats (n = 185). Repeated high frequency, low frequency, or sham transcutaneous electric nerve stimulation (TENS) was performed to the ipsilateral knee joint for 20 min in rats with OA (n = 45). Minocycline or minocycline plus TENS (HF, LF, or sham) was treated in OA rats with repeated TENS-induced tolerance (n = 135). Immunohistochemistry of the microglia in the L3–L5 spinal segments was performed. Knee joint pain during passive movement of the knee joint were quantified using the knee-bend score and the proportion of activated microglia was calculated as primary variables. Paw withdrawal threshold (hypersensitivity to mechanical stimuli) was assessed and the resting and activated microglia were counted as secondary variables. Repeated applications decreased the analgesic effect of TENS on OA pain and failed to reduce the expression of activated microglia in the spinal cord. However, spinal microglial inhibition by minocycline restored the analgesic effect of TENS on OA pain in TENS-tolerant OA rats. TENS combined with minocycline treatment improved knee joint pain and mechanical hypersensitivity in TENS-tolerant OA rats, and inhibited the expression of activated microglia in the spinal cord. These results suggest a possible relationship between repetitive electric stimulation-induced analgesic tolerance for OA pain control and changes in microglia activation.