Central Mechanisms of Itch

Abstract

This chapter summarizes recent findings regarding the central transmission of acute and chronic itch. Itch is transduced by cutaneous pruriceptors that transmit signals to neurons in the superficial spinal cord. Spinal itch-signaling circuits utilize several neuropeptides whose receptors represent novel targets to block itch transmission. Itch is relieved by scratching, which activates spinal interneurons to inhibit itch-transmitting neurons. Spinal itch transmission is also thought to be modulated by descending pathways. Itch is transmitted rostrally via ascending pathways to activate a variety of brain regions involved in sensory discrimination of affective and motor responses to itch. The pathophysiological mechanisms of chronic itch are poorly understood but likely involve sensitization of itch-signaling pathways and/or dysfunction of itch-inhibitory circuits. Improved understanding of central itch mechanisms has identified a number of novel targets for the development of antipruritic treatment strategies.

Peripheral Sensitization and Loss of Descending Inhibition Is a Hallmark of Chronic Pruritus

“…Pruritus also involves the brain, and mapping of a pruritus matrix in healthy volunteers and patients with CP indicated similar but not identical brain networks of pruritus and pain (Carstens and Akiyama, 2016). Interestingly, simultaneous pruritic and painful stimulation activated the periaqueductal gray, which is known for its role in endogenous pain inhibition (Carstens and Akiyama, 2016).…”

“…Pruritus also involves the brain, and mapping of a pruritus matrix in healthy volunteers and patients with CP indicated similar but not identical brain networks of pruritus and pain (Carstens and Akiyama, 2016). Interestingly, simultaneous pruritic and painful stimulation activated the periaqueductal gray, which is known for its role in endogenous pain inhibition (Carstens and Akiyama, 2016). Therefore, endogenous descending inhibition, known to be involved in chronicity of pain (Lewis et al, 2012;Yarnitsky, 2015), might play a role inhibiting pruritus at the spinal level and could possibly be involved in CP.…”

How to define chronic pruritus: Symptom or disease?

“…Quantitative sensory testing, a measurement for neuropathic pain, showed no alterations in chronic prurigo . Signs of itch hypersensitivity are alloknesis (itch elicited by low‐threshold tactile, not‐pruritic stimulus; knesis is the greek word for itching) and hyperknesis (increased itch to a pruritic stimulus). These signs have been linked to itch‐specific mechanisms, for example the altered keratinocyte expression of artemin and of the enzyme 11β‐hydroxysteroid dehydrogenase 1 (HSD‐11β1 that activates endogenous glucocorticoids) in an atopic dermatitis model …”

“…Altered supraspinal processing of non‐histaminergic itch‐signalling nerves and/or dysfunction of itch‐inhibitory circuits resulting in ongoing nerve activity were suggested to be the basis for central sensitization . Central and peripheral neuronal sensitization are considered today to be the mechanistical basis for the persistence and chronicity of pruritus, independent of the underlying disease.…”

Treatments for chronic pruritus outside of the box

“…Some of the receptors are predominantly expressed in the peripheral nervous system and include (apart from H1R and H4R) protease‐activated receptors (eg PAR‐2), Mas‐related G protein‐coupled receptors (eg MrgprX1), neurokinin 1 receptor (NK1R), serotonin receptors (eg 5‐HT2R), endothelin‐1 receptors (eg ET A ), neurotrophin receptors (eg TrkA), bile salt receptor (TGR5) and cannabinoid receptors (eg CB 2 ). Other itch‐related G protein‐coupled receptors are primarily expressed in the central nervous system and include gastrin‐releasing peptide and μ‐ and κ‐opioid receptors . While most of these receptors are involved in inducing pruritus, cannabinoid and κ‐opioid receptors are mainly thought to suppress itch signalling.…”