Aspirin, an ASIC3 inhibitor, blocks the analgesic effect of therapeutic ultrasound in chronic muscle pain

Abstract

Therapeutic ultrasound is widely used in pain control in physical medicine, and substance P (SubP) is the key pathway. However, the ion channels involving the analgesic process are still not clear. The objective of this study is to prove that the mechanism of the analgesic effects of ultrasound in a rodent model of chronic muscle pain is through acid sensing ion channel 3 (ASIC3). We employed the chronic hyperalgesia mouse model proposed by Sluka et al. and applied therapeutic ultrasound at 3 MHz, 100% duty cycle, 1 W/cm 2 for 3 min. Mice were co-injected with pH 4.0 saline and 100 uM RP-67580 on day 0. From days 4 to 8 after the first acid injection, mice were co-injected with pH 7.4 saline and Aspirin (ASP) 500 uM, 5 mM, or ibuprofen (IBU) 500 uM. The withdrawal response of mouse hind paws was defined as foot lifting when a 0.2-mN von Frey filament was applied. ASP diminished the analgesia induced by ultrasound treatment in mouse chronic muscle pain model. However, IBU, inhibitor of ASIC1a, did not. SubP and pERK content increased after ultrasound in DRG. Two minutes after ultrasound, ipsilateral pERK, subP, and tracer were significantly increased and overlapped each other. However, subP increased to less extent. Therapeutic ultrasound and acid injection could inhibit intramuscular nociceptor activation, and result an anti-nociceptive effect against chronic mechanical hyperalgesia through ASIC3 pathway. In the future, small molecule inducing SubP and ASIC3 can be new candidate to treat chronic diffuse muscle pain.