Itch

Pain is a common condition in dermatology. The aim of this review is to analyse the characteristics of pain in dermatology. Some skin diseases are conventionally known to cause pain; e.g. ulcers, pyoderma gangrenosum and herpes zoster. Common dermatoses, such as psoriasis or atopic dermatitis, can also cause significant pain. Some conditions are characterized by neuropathic pain and/or pruritus, without visible primary lesions: e.g. the neurocutaneous diseases, including small fibre neuropathies. Patients often fear pain in skin surgery; however, surgical procedures are rather well tolerated and any pain is mainly due to administration of local anaesthetic. Some therapies may also be uncomfortable for the patient, such as photo-dynamic therapy or aesthetic procedures. Thus, pain in dermatology is common, and its aetiology and charac-teristics are very varied. Knowledge of the different situations that cause pain will enable dermatologists to propose suitable analgesic solutions.

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling.

Despite the high prevalence of chronic dermatitis and the accompanied intractable itch, therapeutics that specifically target itching have low efficacy. Increasing evidence suggests that TLRs contribute to immune activation and neural sensitization; however, their roles in chronic itch remain elusive. Here, we show that the RBL-2H3 mast cell line expresses TLR4 and that treatment with a TLR4 antagonist opposes the LPS dependent increase in mRNA levels of Th2 and innate cytokines. The pathological role of TLR4 activation in itching was studied in neonate rats that developed chronic itch due to neuronal damage after receiving subcutaneous capsaicin injections. Treatment with a TLR4 antagonist protected these rats with chronic itch against scratching behavior and chronic dermatitis. TLR4 antagonist treatment also restored the density of cutaneous nerve fibers and inhibited the histopathological changes that are associated with mast cell activation after capsaicin injection. Additionally, the expression of IL-1β, IL-4, IL-5, IL-10, and IL-13 mRNA in the lesional skin decreased after TLR4 antagonist treatment. Based on these data, we propose that inhibiting TLR4 alleviated itch in a rat model of chronic relapsing itch, and the reduction in the itch was associated with TLR4 signaling in mast cells and nerve fibers.

Central neuropathic pain is a core clinical sign of syringomyelia in humans and Cavalier King Charles Spaniel (CKCS) dogs. This histopathological study used spinal cords from CKCS with syringomyelia to investigate: 1) whether specific structural cervical spinal cord entities involved in nociception are affected by loss of neuroparenchyma or other pathological changes in CKCS with pain-related behaviour and phantom scratching, 2) if pain related behaviour or phantom scratching correlated with loss of a specific anatomical entity or upregulation of glia cells, and 3) if syringomyelia-related lesions affected specific functional spinal cord units of nociception.Spinal cord segments C1-C8 from CKCS with MRI-confirmed syringomyelia and clinical signs of pain and phantom scratch (n=8) were compared to CKCS without syringomyelia (n=4). Dogs with unilateral scratching (n=7) had a volume loss (P=0.043) of the dorsal horn laminae I-III in the ipsilateral side compared to the contralateral dorsal horn. A clear pattern of ipsilateral changes in the dorsal root entry zone characterised by deafferentation and reorganization of first-order axons into deeper laminae was found in cases with lateralised scratching. Significant changes in cell number density were not found for astrocytes or microglia, suggesting that the dogs represented cases of end-stage syringomyelia and thus could not reveal astrogliosis and microgliosis, which may be involved in the early phases of syrinx development and phantom scratch.The present relationship between clinical findings and dorsal horn and pain pathway pathology in CKCS suggests that these dogs may be of interest as a supplement to experimental model pain research.

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating two of our largest organs, the nervous and immune system. Dysregulation of neuro-immune circuits plays a key role in the pathophysiology of AD causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors transmitting itch stimuli to the brain. Upon stimulation, sensory nerve endings also release neuromediators into the skin contributing again to inflammation, barrier dysfunction and itch. Additionally, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, neuropathic itch, thus chronification and therapy-resistance. Consequently, neuro-immune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, ions excite/sensitize sensory nerve endings not only induce itch but further aggravate/perpetuate inflammation, skin barrier disruption, and pruritus. Thus, targeted therapies for neuro-immune circuits as well as pathway inhibitors (e.g., kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or topical form. Understanding neuro-immune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction and pruritus.

Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety of purinergic effectors, and a variety of receptors play critical roles in the pathogenesis of neuropathic pain. In this review, we discuss our current knowledge of purinergic signaling and of the compounds that modulate purinergic transmission, with the aim of highlighting the importance of purinergic pathways as targets for the treatment of persistent pain.

Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head.