Abstract
Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.
Highlights
Pain is an essential physiological response, warning of current or possible tissue damage, and is modulated by psychological, emotional, and societal components [1]
In addition to peripheral neuropathy, central neuropathic pain can occur as a result of damage to the central nervous system (CNS), including stroke, encephalitis, and demyelinating disease like multiple sclerosis [10]
Inflammatory pain, such as that caused by diseases like arthritis, involves tissue damage that results in the recruitment of immune cells and subsequent release of proinflammatory substances, including cytokines and adenosine 5′-triphosphate (ATP)
Summary
Pain is an essential physiological response, warning of current or possible tissue damage, and is modulated by psychological, emotional, and societal components [1]. In addition to peripheral neuropathy, central neuropathic pain can occur as a result of damage to the central nervous system (CNS), including stroke, encephalitis, and demyelinating disease like multiple sclerosis [10] Inflammatory pain, such as that caused by diseases like arthritis, involves tissue damage that results in the recruitment of immune cells and subsequent release of proinflammatory substances, including cytokines and adenosine 5′-triphosphate (ATP). Both neuropathic and inflammatory pain are associated with an elevated sensitivity to innocuous stimuli (such as warm water or changing clothes), as well as hypersensitivity to noxious stimuli, referred to as allodynia and hyperalgesia, respectively [11]. We will describe the emerging role of these large-pore channels as conduits of ATP release during nociceptive signaling (Fig. 1)
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