Neuroreceptors and Mediators


  • Calcitonin gene-related peptide (CGRP) has an impact on keratinocyte (the protective barrier cells/early warning system of the skin) differentiation, cytokine expression, and apoptosis through intracellular nitric oxide (NO) modulation and stimulation of nitric oxide synthase (NOS) activity
  • Stimulation of cultured human melanocytes with CGRP, SP, or vasoactive intestinal peptide (VIP) led to increased DNA synthesis rate of melanocytes by the cAMP pathway in a concentration- and time-dependent manner mediate

Some Important part to note

  • Substance P – induces release of histamine via binding to NKR on mast cells
  • VIPneurotensin and secretin also stimulate histamine release
  • Somatostatin stimulates histamine release from human mast cells
  • NGF stimulates histamine release and senstizes transient receptor potential V1 (TrpV1)
  • mast cell activation and histamine are required for normal wound healing (probably not chronic though)
  • Ketotifen Fumarate – h1 antagonist and mast cell growth inhibitor

Substance P (SP)

  • It induces release of histamine
  • It upregulates intercellular adhesion molecule 1 (ICAM-1), which is chemotactic for neutrophils
  • It also induces release of IL2 or IL6
  • histamine regulates SP via H3 receptors on sensory nerves
  • NGF and SP are downregulated after chronic use of capsaicin (to decrease itching and pain)

Mast cells

  • Endothelin (ET) -1, -2, and -3 work on mast cells and binds to ETA and ETB
  • ET1 degranulates mast cells (TNFa IL6 VEGF and TGFB1)
  • ET1 is involved with UV radiation (such as tanning) or inflammation of mast cells
  • Have CB1 and CB2 (also on T-lymphocytes)receptors


  • TrpV helps skin barrier homeostasis
    • TrpV1 is the capsiacin receptor
    • TrpV1 is also called vanilloid receptor (VR1)
    • TrpV1 can be activated by bradykinin, prostaglandins, and NGF
    • TrpV1 can be actvated by heat
  • CB1 agonist anandamide binds to the TrpV1 receptor
    • Topical cannabinoids directly inhibit TrpV1 functional activities via a calcineurin pathway
  • TrpV2, V3, and V4 are activated by warmth/heat
    • TrpV2 by >52C, TrpV3, >33C and TrpV4 ~25C
    • TrpV4 also acts on cold recptors creating a cold feeling (by binding camphor)
    • TrpM8 (CMR1) can be stimulated by 8-28C, menthol, or icillin
  • TrpA1 (ANKTM1) van be stimulated by <17C, wasabi, horseradish, mustard, bradykinine, or THC
  • Cooling skin temperature (or using menthol) reduces itch via inhibitory effect of Aδ-fiber activation
    • Cold sensation occurs by NGF increasing TrpA1 receptors on nerve fibers
  • In the DRG, exposure to GDNF, neurturin, or artemin potentate TrpV1 function at doses 10–100 times lower than NGF.

Proteinase-Activated Receptors

  • proteinase-activated receptor-2 (PAR-2) is activated by tryptase(and other mast cell mediators) and mast cells express PAR-2
  • Activation of PAR-2 causes inflammation similar to histamine release and can cause pain

Opioid Receptors

  • There are 2 receptors, μ- and δ-receptor, found in sensory nerve ffibers
    • β-endorphin, enkephalins, and endomorphins act on capsaicin-sensitive nerve fibers to inhibit the release of inflammatory neuropeptides such as SP, neurokinin A, and CGRP
  • Opioids mediate pain response (via mechanical and thermal stimuli)
  • Morphine works on mu- and to a lesser extent kappa- and delta-opioid receptors

Cannabinoid Receptors

  • CB system can treat pain
    • CB2 agonist palmitoylethanolamine (PEA) inhibits NGF induced thermal pain, but can be inhibitied by naloxone
    • cannabinoid agonist AM1241 stimulates β-endorphin release

Nerve Growth Factor

  • Nerve growth factor regulates skin homeostasis and inflammation
    • Pain induces NGF production and release sending signals from the skin to the dorsal root ganglia (DRG) which promotes neuronal growth and sensitivity
    • NGF can enhance caspacin evoked thermal pain
    • NGF is over expressed in many chronic illnesses with pain as well as allergic diseases


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