Why Skin Matters

Author: Frank L. Rice, Phillip J. Albrecht, & Charles E. Argoff

Skin is the largest sensory organ in the body and maintains the greatest contact with our external world. As such, skin acts as both an essential physical barrier and an exquisite detection system. Skin is highly adaptable, self-restorative, and provides structural and biochemical functions that participate in essential neural, vascular, endocrine, and immune system regulation. Furthermore, skin directly represents an external expression of internal functioning (eg, rash or blushing), and psychologically, when humans see themselves and others, the skin conveys an immediate impression of health (and attractiveness). Constant exposure to changing external and internal environmental conditions, including numerous physical, chemical, bacterial/viral, and UV insults can alter the complex functionality of skin, and many organic disorders and responses to exogenous substances result in a range of debilitating skin abnormalities and/or neurological afflictions, such as psoriasis or peripheral neuropathy. Importantly, intractable chronic pain conditions, pruritus (itch), and/or numbness are often accompanied by pathologies among the wide variety and dense distributions of skin neural innervation. Therefore, skin biopsy evaluations are becoming an important means of detecting pain-associated pathologies, particularly small fiber neuropathy, and identifying additional altered mechanisms which can be targeted to develop novel therapeutic strategies, including topical analgesics. This article reviews cutaneous (skin) mechanisms of chronic pain and highlights the emerging value of multimolecular skin biopsy analysis in patients with a variety of chronic pain conditions.

Chronic Pain Remains a Clinical Challenge

Chronic pain, including that from arthritis, neuropathic pain (np), and idiopathic conditions, can be broadly characterized as maladaptive disorders of the peripheral and/or central somatosensory nervous system with known involvement of the immune, endocrine, and limbic systems. These disorders severely impair the health and quality of life in approximately 30% to 35% of the population, with np alone having an estimated economic impact at over $60 billion annually in the United States. Under normal conditions, painful sensations are beneficial and adaptive in that they serve to protect individuals from potentially dangerous or damaging tissue injury and promote healing by limiting use of injured body structures. Pain is a conscious sensation generated at the cortical level, but represents a culmination of direct stimulus detection processing (and physiologic response) regarding intensity, location, and quality, which is tempered with limbic (emotionality) activity regarding the situational context and environment. Pain is an individually unique sensation and can be qualitatively different across similar individuals, or even among the same individual at different times. This complex neural interplay makes treating chronic pain conditions notoriously difficult, despite having rather good control of acute pain treatment in the clinic.

The pathways which are activated in response to stimuli that produce painful human responses (noxious stimuli) are termed nociceptive (noci = pain) pathways. The predominant theory is that some types of primary afferent sensory neurons of the dorsal roots and trigeminal ganglia, termed primary nociceptors, specifically respond to noxious stimuli and transmit the nociceptive signal from the periphery to the spinal cord. Nociceptors innervate nearly all tissues of the body as small caliber, thin, unmyelinated or lightly-myelinated axons and are particularly concentrated in the outermost layer of skin, the epidermis. These cutaneous nociceptive endings respond to extreme temperatures, mechanical stresses, chemicals, bacterial/ viral proteins, and UV radiation stimuli to drive the sensation of pain (and/or itch). Acute pain occurs when stressors or ongoing tissue damage cause a high level of activity among these nociceptors. A variety of therapeutics can effectively treat acute pain by blocking different types of molecules (cytokines) released by traumatized and inflamed tissues that activate nociceptors, or by blocking different types of molecules that enable nociceptors to respond to cytokines and additional stimuli. Acute pain (by definition) lasts only for the "short" time that tissue damage requires to heal, presumably after which activity in the nociceptors decreases back to normal. However, many people develop chronic pains that last well beyond the time of normal tissue healing after disruption, or in some incidences without known provocation. Currently, the mechanisms underlying chronic pain development and maintenance remain obscure, despite much research.

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