Abstract
Pain is a dominant symptom of rheumatoid arthritis (RA) and its adequate treatment represents a major unmet need. However, the cellular mechanisms that drive arthritis pain are largely unexplored. Here, we examined the changes in the activity of joint sensory neurons and the associated ionic mechanisms using an animal model of antigen-induced arthritis (AIA). Methylated-bovine serum albumin (mBSA), but not vehicle challenge, in the ankle of previously immunized mice produced time-dependent symptoms of arthritis, including joint inflammation, primary mechanical hyperalgesia in the ipsilateral ankle, and secondary mechanical and heat hyperalgesia in the ipsilateral hindpaw. In vivo electrophysiological recordings revealed that Dil-labeled joint sensory neurons in AIA mice exhibited a greater incidence of spontaneous activity, mechanically evoked after-discharges, and/or increased responses to mechanical stimulation of their receptive fields, compared to control animals. Whole-cell recordings in vitro showed that AIA enhanced the excitability of joint sensory neurons. These signs of neuronal hyperexcitability were associated with a significant reduction in the density of A-type K+ currents. Thus, our data suggest that neuronal hyperexcitability, brought about in part by reduced A-type K+ currents, may contribute to pain-related behaviors that accompany antigen-induced arthritis and/or other antigen-mediated diseases.
Highlights
Channels[11,14,15]
Kv currents recorded from dorsal root ganglion (DRG) neurons consists of two major subtypes, transient A-type K+ currents (IA) and sustained delayed rectifier K+ currents (IK), both of which have been implicated in the generation of pain sensation[18]
Our study focused on pain-related behaviors and changes in the excitability of joint sensory neurons following Antigen–induced arthritis (AIA)
Summary
Channels[11,14,15]. spontaneous activity (SA) and increased mechanical sensitivity were observed in joint sensory afferents in a rat model of osteoarthritis, and were implicated in the maintenance of osteoarthritis pain[16,17]. There is increasing evidence that the expression and activity of Kv channels in primary sensory neurons are downregulated under inflammatory and neuropathic pain conditions and that these channels are involved in the maintenance of a chronic pain state[20,21,22]. Consistent with this notion, CFA- induced joint inflammation produced downregulation of A-type K+ channels in joint-innervating sensory neurons, possibly contributing to mechanical allodynia in the inflamed joint[23,24]. We investigated the possibility of alterations in K+ channels in joint sensory neurons in this model
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