Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia.

BACKGROUND: Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown. RESULTS: Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days). CONCLUSION: ASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain.

Neurosensory mechanotransduction through acid-sensing ion channels.

Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels responding to extracellular acidification. ASIC proteins have two transmembrane domains and a large extracellular domain. The molecular topology of ASICs is similar to that of the mechanosensory abnormality 4- or 10-proteins expressed in touch receptor neurons and involved in neurosensory mechanotransduction in nematodes. The ASIC proteins are involved in neurosensory mechanotransduction in mammals. The ASIC isoforms are expressed in Merkel cell-neurite complexes, periodontal Ruffini endings and specialized nerve terminals of skin and muscle spindles, so they might participate in mechanosensation. In knockout mouse models, lacking an ASIC isoform produces defects in neurosensory mechanotransduction of tissue such as skin, stomach, colon, aortic arch, venoatrial junction and cochlea. The ASICs are thus implicated in touch, pain, digestive function, baroreception, blood volume control and hearing. However, the role of ASICs in mechanotransduction is still controversial, because we lack evidence that the channels are mechanically sensitive when expressed in heterologous cells. Thus, ASIC channels alone are not sufficient to reconstruct the path of transducing molecules of mechanically activated channels. The mechanotransducers associated with ASICs need further elucidation. In this review, we discuss the expression of ASICs in sensory afferents of mechanoreceptors, findings of knockout studies, technical issues concerning studies of neurosensory mechanotransduction and possible missing links. Also we propose a molecular model and a new approach to disclose the molecular mechanism underlying the neurosensory mechanotransduction.

Targeting ASIC3 for pain, anxiety, and insulin resistance.

The acid-sensing ion channel 3 (ASIC3) is a pH sensor that responds to mild extracellular acidification and is predominantly expressed in nociceptors. There is much interest in targeting ASIC3 to relieve pain associated with tissue acidosis, and selective drugs targeting ASIC3 have been used to relieve acid-evoked pain in animal models and human studies. There is accumulating evidence that ASIC3 is widely expressed in many neuronal and non-neuronal cells, such as neurons in the brain and adipose cells, albeit to a lesser extent than in nociceptors. Asic3-knockout mice have reduced anxiety levels and enhanced insulin sensitivity, suggesting that antagonizing ASIC3 has additional benefits. This view is tempered by recent studies suggesting that Asic3-knockout mice may experience cardiovascular disturbances. Due to the development of ASIC3 antagonists as analgesics, we review here the additional benefits, safety, risks, and strategy associated with antagonizing ASIC3 function.