Substance P is a neuropeptide (neurotransmitter) most known for its role in pain perception. It also has a wide range of effects in nausea, stress responses, emotional behavior, learning, and memory.
However, although substance P is important for survival, excess levels are harmful and can lead to a variety of diseases. Read more to learn about what conditions are associated with high and low levels of substance P and how to increase and decrease it.
Substance P was first isolated from horse brain and gut extracts in the 1930s as a mystery substance with strong blood pressure-lowering and smooth muscle contractile properties [ 1 ].
Because it was in powdered form, it was named substance P (“P” for powder) [ 1 ].
Today, it is fully recognized as a neurotransmitter that is widely dispersed throughout the body, with high levels in the brain, gut, and spinal cord [ 1 , 2 ].
Because of its broad distribution in the body, substance P influences a diverse range of functions. It also amplifies or excites most cellular processes [ 3 ].
Substance P is involved in:
Most actions of Substance P’s binding to NK-1 (neurokinin receptor subtype) receptors mediate its actions. The receptors are found in a variety of cell types (e.g., neurons, muscle cells, immune cells) [ 13 ].
The cell quickly takes NK1 receptors back up after substance P binding. The cells remove and break down substance P, while NK-1 receptors are recycled to the cell membrane [ 14 ].
Substance P and the NK-1 receptor have been extensively researched for their role in a variety of diseases [ 15 ].
Drugs that block Nk1 receptors have been used to treat mood disorders ( depression , anxiety , and stress), nausea from chemotherapy, rheumatoid arthritis, and inflammatory bowel disease [ 15 , 16 ].
Substance P levels are increased in stressful or anxiety-provoking situations [ 17 ].
Stressful stimuli like heat and pain trigger the release of substance P from sensory nerve endings. The amount of its release is proportional to the intensity and frequency of stimulation [ 17 ].
Once released, substance P may have direct actions as a neurotransmitter or other functions on non-nerve cell targets [ 14 ].
It can also be cleared and inactivated by enzymes that break down proteins (e.g., NEP and ACE) [ 18 , 19 ].
Substance P is a powerful vasodilator (widens blood vessels) of large blood vessels in animals and humans [ 20 , 21 ].
It widens blood vessels by binding to NK1 receptors on the vessel wall and causing the release of nitric oxide [ 22 ].
Unlike other neurotransmitters, vasodilation caused by substance P declines during continuous injection. This is likely due to the rapid internalization of Nk1 receptors after activation [ 23 ].
Substance P helps transmit pain signals from different parts of the body to the spinal cord and brain (where the pain is perceived) [ 24 , 25 , 26 ].
Specifically, sensory nerve fibers (i.e., primary afferent nerve fibers) detect pain and release substance P, which in turn binds to Nk-1 receptors in the spinal cord. Nerve cells in the spinal cord then relay the pain information to the brain [ 27 , 28 ].
Substance P also increases sensitivity to pain indirectly by its inflammatory effects (swelling, immune cell recruitment, vasodilation) [ 29 ].
Interestingly, in some studies, substance P has a pain-relieving effect . For example, in mice with acid-induced chronic muscle pain, substance P reduced pain by decreasing the detection of pain signals in muscle sensory neurons [ 30 ].
This dual role of substance P in pain management may explain why drugs that block Nk-1 receptors have been unsuccessful in relieving pain in clinical trials [ 25 , 31 , 32 ].
Substance P is secreted by many inflammatory immune cells (i.e., macrophages, eosinophils , lymphocytes , and dendritic cells) and initiates the production of inflammatory cytokines (IL-1β, IL-6, and IL-8) [ 33 , 34 , 7 ].
In turn, most cytokines bind to substance P and NK-1 receptors [ 35 ].
Substance P causes brain inflammation , a local inflammatory response to some types of infection or injury [ 36 ].All of these effects are mediated by the Nk-1 receptor [ 37 , 38 ].Substance P has excitatory effects in the hippocampus or the memory center of the brain. It promotes long-term potentiation, which is associated with learning and the formation of memories [ 39 , 40 , 41 ].Moreover, injection of substance P in parts of the brain that control motivation and reward facilitated learning and memory in rats [ 42 , 43 ].Substance P stimulated the growth of nerve stem cells of adult rats under both normal conditions and during injury. It may help with nerve cell formation after injury [ 44 ].Substance P and its receptor are present in high levels in the Area Postrema (the vomiting center in the medulla) along with other neurotransmitters (e.g., choline , histamine, dopamine ) [ 45 ].It activates the NK-1 receptors. Applying substance P in the vomiting center of the brain causes dry heaving in ferrets [ 46 , 47 , 48 ].Drugs that block Nk1 receptors can help treat nausea associated with chemotherapy [ 6 ].Substance P (injected in the skin) causes an itch sensation in human skin by stimulating histamine release from mast cells [ 49 ].Substance P also causes scratching behavior in mice but through mechanisms independent of histamine [ 50 , 51 ].Substance P accelerated wound healing in the eyes (in rabbits) and spinal cord (in rats) by promoting a local inflammatory response essential for healing [ 52 , 53 , 54 ]. Conditions with Elevated Substance P Patients with eczema have higher blood levels of substance P [ 55 ].Substance P causes mast cell accumulation and inflammation, which is involved in the development of eczema. Mast cells are white blood cells that play a role in allergic and inflammatory reactions [ 55 ].Because of its role in inflammation and cell growth, substance P can contribute to psoriasis progression . Psoriasis skin and patches have an increased […]