D38: detailed overview of receptors in the skin endocannabinoid system

Unraveling the Skin’s Endocannabinoid System: A Comprehensive Exploration of Skin Receptors, Penetration Facilitators, and Their Multifaceted Roles


The skin, our body’s largest organ, is not just a protective barrier but a dynamic ecosystem rich with receptors and signaling pathways. Among its many regulatory systems, the skin boasts an endocannabinoid system (ECS) that plays an integral role in maintaining skin homeostasis. In this detailed overview, we embark on a journey through the intricate layers of the skin, uncovering the diverse receptors within the skin’s ECS. We’ll also delve into compounds known to facilitate skin penetration and the profound effects of temperature, moisture, and other factors on the skin’s nerves, blood vessels, stem cells, and fat cells.

Navigating the Skin’s Layers: A Receptor-Rich Landscape


  1. CB1 and CB2 Receptors: Both CB1 and CB2 receptors are present in the epidermis, influencing various aspects of skin health. CB1 receptors play a role in regulating sebum production and immune responses, while CB2 receptors contribute to immune modulation and anti-inflammatory effects.


  1. Vanilloid Receptors (TRPV1): These receptors, sensitive to temperature and certain compounds, are found in the dermis and play a role in pain perception and temperature regulation in the skin.
  2. Opioid Receptors: Mu and delta opioid receptors have been identified in the dermis, where they may participate in pain modulation and the regulation of skin functions.


  1. Adenosine Receptors: The hypodermis houses adenosine receptors, which have implications for regulating blood flow, fat metabolism, and anti-inflammatory responses in the skin.
  2. Purinergic Receptors: Purinergic receptors, specifically P2X3 and P2X5, are expressed in the hypodermis and may contribute to pain sensation and sensory nerve functions.

Facilitating Skin Penetration: Compounds of Interest

  1. Terpenes: Terpenes found in cannabis, such as limonene and myrcene, possess the ability to enhance the penetration of substances through the skin’s layers, potentially aiding in the delivery of therapeutic compounds.
  2. Fatty Acids: Fatty acids like oleic acid can assist in the permeation of substances through the skin, offering opportunities for improved topical drug delivery.

Temperature, Moisture, and Their Impact

  1. Temperature: Temperature fluctuations can influence skin blood flow, affecting the delivery of nutrients and the removal of waste products. Additionally, temperature-sensitive receptors like TRPV1 play a role in pain perception and temperature regulation in the skin.
  2. Moisture: Proper skin hydration is vital for maintaining its barrier function. Changes in moisture levels can impact the skin’s permeability and susceptibility to external factors.

Effects on Nerves, Blood Vessels, Stem Cells, and Fat Cells

  1. Nerves: Temperature-sensitive receptors like TRPV1 are involved in pain sensation and thermal regulation in the skin. Modulating these receptors has therapeutic potential for managing pain and temperature-related skin conditions.
  2. Blood Vessels: Adenosine receptors in the hypodermis are linked to blood flow regulation, suggesting a role in wound healing and vascular function.
  3. Stem Cells: The skin’s stem cells are crucial for tissue regeneration and repair. Manipulating the ECS and associated receptors may have implications for enhancing skin regeneration.
  4. Fat Cells: Adipose tissue in the hypodermis, with its adenosine receptors, is interconnected with metabolic processes and inflammation in the skin. Targeting these receptors could offer insights into managing skin conditions related to adipose tissue.


The skin’s ECS, with its intricate web of receptors, compounds, and environmental factors, stands as a testament to the remarkable complexity of this organ. Understanding the roles of these receptors and their interactions in the various skin layers provides a foundation for developing innovative approaches to skin health, pain management, and topical drug delivery.

References: (Due to character limitations, a selection of key references is provided here; further exploration in scientific literature is encouraged)

  • Pucci, M., Pasquariello, N., Battista, N., & Di Tommaso, M. (2013). Endocannabinoids in the skin. In Cannabinoids in Neurologic and Mental Disease (pp. 131-136). Academic Press.
  • Sarnataro, D., Pisanti, S., Santoro, A., & Gazzerro, P. (2016). The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Molecular Pharmacology, 90(2), 252-259.
  • **Borrelli, F., Pagano, E., Romano, B., Panzera, S., Maiello, F., Coppola, D., … & Izzo, A. A. (2014). Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis, 35(12), 2787-2797.**
  • Katsuyama, S., Mizoguchi, H., Kuwahata, H., Komatsu, T., Nagaoka, K., Nakamura, H., … & Itoh, T. (2013). Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. European Journal of Pain, 17(5), 664-675.

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