ReviewNeuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms?
Introduction
Itch and pain are closely related but distinct sensations. Itch (pruritus) elicits scratching response, whereas pain causes withdrawal responses. In physiological conditions, acute itch can be inhibited by scratching and painful stimuli. The antagonistic interaction between itch and pain is further revealed by the fact that analgesic compounds such as morphine and bile acid can evoke itch [1], [2]. Itch and pain also share similarities, especially in pathological and chronic conditions [3]. Both itch and pain are detected by primary sensory neurons in dorsal root ganglion (DRG) and trigeminal ganglion. Indeed, pruriceptors and nociceptors are overlapped in DRGs, and the pruriceptors are a subset of small population of C-fiber nociceptors. Pain and itch also employ largely overlapping transduction machinery, such as transient receptor potential ion channel subtype V1 (TRPV1) and A1 (TRPA1), Toll-like receptors (TLRs), and proteinase activated receptors (PARs), although the G-protein coupled receptor (GPCR) MrgprA3 and thymic stromal lymphopoietin (TSLP) receptor are identified as itch-specific receptors [4], [5]. Under pathological and chronic conditions, dysfunction of the nervous system, as manifested by neural plastic changes in primary sensory neurons of the peripheral nervous system (peripheral sensitization) and spinal cord, brain stem, and cortical neurons in the central nervous system (central sensitization) will not only result in chronic pain but also lead to chronic itch [3], [6]. For example, central sensitization underlies both touch-evoked pain (allodynia) and touch-evoked itch (alloknesis) [7], [8]. Loss of inhibitory synaptic transmission (disinhibition) in the spinal cord has also been attributed to both chronic pain and chronic itch; both can be suppressed by spinal implantation of forebrain GABAergic neurons [9], [10]. Importantly, both diseases are a direct consequence of immune dysfunction, since inflammatory mediators, produced by immune cells and epithelial cells after tissue injury, can directly activate or sensitize nociceptive and pruriceptive neurons, leading to pain and itch hypersensitivity [3], [11]. I focus this review on emerging roles of TLRs, TRPA1, and Nav1.7 in the regulation of pain, itch, and neuroinflammation, an inflammation that is restricted in the nervous system but is particularly important for the pathogenesis of neurological diseases [12]. Finally, I also discuss the shared mechanisms and treatments among chronic pain, chronic itch, and chronic cough.
Section snippets
Itch mediators and transduction mechanisms
As one of the best studied itch mediators, histamine is released from mast cells and binds to histamin H1 receptor (H1R), which is coupled with Gαq, phospholipase Cβ3, and TRPV1 in DRG neurons to evoke itch [13], [14]. Although antihistamines are widely-used as anti-itch drugs, chronic itch is often resistant to anti-histamine treatments [15]. It is generally believed that unmyelinated C-fibers especially TRPV1-expressing C-fibers are responsible for generating both histamine dependent and
Emerging roles of TLRs in pain, itch, and neuroinflammation
TLRs are typically expressed in immune cells to mediate innate immunity by recognition of pathogen-associated molecular patterns (PAMPs) [33]. Most TLRs (except TLR3) requires the intracellular adaptor protein MyD88 (myeloid differentiation primary response gene 88) to mediate down-stream signaling via activation of NF-κB and MAP kinase pathways [34], [35], leading to the synthesis of a wide range of inflammatory mediators, including cytokines, chemokines, and reactive oxygen/nitrogen
Do chronic itch, chronic pain, and chronic cough share similar mechanisms?
Despite clear differences between acute pain and acute itch, chronic pain and chronic itch share similar mechanisms, including peripheral sensitization, central sensitization, and glial and immune regulation [3], [12], as illustrated in Fig. 2. Peripheral sensitization can be induced by inflammatory mediators produced after tissue injury and requires the activation of TRPA1 and Nav1.7, as well as TRPV1 and Nav1.8 [54]. While activation of TLRs in non-neuronal cells produces inflammatory
Concluding remarks and future directions
It is well established that chronic pain is a hypersensitivity state that results from peripheral and central sensitization [6], [54]. It is increasingly appreciated that chronic itch and chronic cough are also hypersensitivity syndromes [3], [71]. While the role of glial cells in the pathogenesis of chronic pain is well recognized [59], their involvement in chronic itch and chronic cough needs further investigation. However, inflammation and neuroinflammation have been implicated in the
Financial interest
The author has no financial interest in this study.
Acknowledgment
This work is supported by NIH RO1 grants DE17794, DE22743, NS87988, and NS89479 to R.R.J.
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