The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation

Abstract

Chronic muscle pain affects between 11 and 24% of the world's population with the majority of people experiencing musculoskeletal pain at some time in their life. Acid sensing ion channels (ASICs) are important sensors of modest decreases in extracellular pH that occur within the physiological range. These decreases in extracellular pH occur in response to inflammation, fatiguing exercise, and ischemia. Further, injection of acidic saline into muscle produces enhanced nociceptive behaviors in animals and pain in human subjects. Of the different types of ASICs, ASIC3 and ASIC1 have been implicated in transmission of nociceptive information from the musculoskeletal system. The current review will provide an overview of the evidence for ASIC3 and ASIC1 in musculoskeletal pain in both inflammatory and non-inflammatory models. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

Keywords: ASIC; Acid; Inflammation; Joint; Muscle; Pain; Proton.

Figure 1

This figure shows data from human subjects where pH 5.2 acidic buffer was infused into the tibialis anterior muscle and compared to saline controls. The infusion was started at time 9 and continued for 15 minutes. Pain ratings at the site of infusion and in the referred pain site (A), drawings of area pain felt by subject (B) and pressure pain thresholds at the site of infusion and in the referred pain site (C) were measured. A. Pain intensity ratings in the group infused with acidic buffer averaged around 2.5–3.0/10 during the infusion for the primary site of pain, and about 1/10 in the referred pain site at the ankle. B. The primary pain site occurred at the infusion site. A portion of the subjects, approximately 60%, had pain referred to the ankle, while 40% had only localized pain. C. Pain thresholds were significantly decreased from baseline during infusion of acidic buffer at both the site of infusion, primary hyperalgesia, and in the referred pain site, secondary hyperalgesia. Figures and data were redrawn from [18].

Figure 2

A. Shows localization of ASIC3 (red) in dorsal root ganglia cells. ASIC3 is immunohistochemically stained and shows as red. The first panel also shows localization of P2X3 (green) and the second also shows localization of TRPV1 (green). The overlap between ASIC3 expression and either P2X3 or TRPV1 (yellow) is shown graphically in the pie chart shows the representation in terms of percentages. Notice minimal overlap with P2X3 and some overlap with TRPV1. Figure reproduced from [6]. B. Bar graphs show the percentage of dorsal root ganglia cells that express ASIC3 currents (Ephys) or protein (Immuno) retrogradely labeled from either the skin or the muscle. Notice that neurons innervating muscle have a higher percentage cells expressing ASIC3 than those innervating skin. Figure reproduced from [6]. C. Summary of the degree of hyperalgesia in different animal models of pain from ASIC3−/− mice when compared to ASIC3+/+ mice. Primary hyperalgesia was assessed by testing the site of the inflammation for response to mechanical stimulation, while secondary hyperalgesia was assessed by examining the responses of a site distant to the site of insult. Paw inflammation (Paw Infl) was induced by 3% carrageenan subcutaneously into the hindpaw and mechanical stimulation was applied to the inflamed paw. Joint inflammation (Joint Infl) and muscle inflammation (Muscle Infl) were induced by injection of 3% carrageenan into the knee joint or gastrocnemius muscle, respectively. Collagen-antibody-induced arthritis was induced by systemic administration of collagen type II antibodies and is used to mimic rheumatoid arthritis presenting with distal swelling and inflammation. Non-inflammatory hyperalgesia was induced by repeated acid injections into the gastrocnemius muscle ((Muscle Acid). Primary hyperalgesia in these deep tissue models was assessed by squeezing the joint (knee or ankle) or muscle with tweezers to obtain a withdrawal response from the site of injury. Secondary hyperalgesia in these models was assessed by examining mechanical sensitivity of the skin at the paw. No hyperalgesia is designated as a “0”. Notice that ASIC3−/− show no differences when measuring primary hyperalgesia in inflammatory models. On the other hand ASIC3−/− mice all show reduced hyperalgesia in tests examining secondary hyperalgesia in multiple musculoskeletal pain models. Data taken from multiple manuscripts [8,10,29,30,35]. D. Current amplitude to decreases doses of pH in dorsal root ganglia cells innervating muscle in the non-inflammatory hyperalgesia model. Responses were assessed 24h after the first injection of pH 4.0 saline into the muscle and 24h after the second injection of pH 4.0 saline into the muscle compared to controls injected with pH 7.2 and uninjected controls. No changes were observed in current amplitude in this model. Data reproduced with permission of Elsevier [15]. E. Current amplitude to decreased doses of pH in dorsal root ganglia innervating muscle 24h after induction of muscle inflammation with 3% carrageenan when compared to uninjected controls or controls injected with normal saline. Notice a significant increase in the current amplitude to decreasing doses of pH in the cells from animals with muscle inflammation. *, p<0.05. Figure reproduced from [14].