Substance P in Fibromyalgia ,High Levels Lead to Excess Pain

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Substance P role in fibromyalgia

Substance P is a neurotransmitter, or brain chemical, that stimulates pain receptors in the body. If a person’s substance P levels are elevated, his or her perception of pain may be greatly exaggerated. Some scientists have investigated whether high levels of substance P play a role in the pain associated with fibromyalgia.

Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis) has been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms.

Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body’s stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia.

As outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.

Affect on people with fibromyalgia

Research suggests that some people with fibromyalgia may have elevated levels of substance P. This is believed to be one of several abnormalities in the nervous system that work together to increase pain sensitivity in the condition, a process that’s often referred to as “turning up the volume” on pain.

Substance P often functions as a neurotransmitter, which means that it communicates signals from one brain cell to another. It’s one of several neurotransmitters believed to be dysregulated in fibromyalgia. An example of heightened pain sensitivity, which could involve a higher than normal level of substance P, is a common fibromyalgia symptom called allodynia.

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Allodynia is the medical term for pain caused by something that normally wouldn’t cause pain. In fibromyalgia, a common source of allodynia is light pressure from clothing. The pain can come from a waistband, even if it’s not tight; a bra strap; or the elastic in your socks. Most people wouldn’t experience pain from these things, but people with fibromyalgia do.

Substance P Widens Blood Vessels

Substance P is a powerful vasodilator (widens blood vessels) of large blood vessels in animals and humans, It widens blood vessels by binding to NK1 receptors on the vessel wall and causing the release of nitric oxide. Unlike other neurotransmitters, vasodilation caused by P-substance declines during continuous injection. This is likely due to the rapid internalization of Nk1 receptors after activation.

SubstanceP Activation

Substance P levels are increased in stressful or anxiety-provoking situations. 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. Once released, substance-P may have direct actions as a neurotransmitter or other functions on non-nerve cell targets. It can also be cleared and inactivated by enzymes that break down proteins (e.g., NEP and ACE).

Substance P Plays a Dual Role in Pain Management

Substance P helps transmit pain signals from different parts of the body to the spinal cord and brain (where the pain is perceived). Specifically, sensory nerve fibers (i.e., primary afferent nerve fibers) detect pain and release P-substance, 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.

Substance P also increases sensitivity to pain indirectly by its inflammatory effects (swelling, immune cell recruitment, vasodilatation. Interestingly, in some studies, substance P has a pain relieving effect. For example, in mice with acid-induced chronic muscle pain, P-substance reduced pain by decreasing the detection of pain signals in muscle sensory neurons.

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.

Influence of tropisetron on the serum substance P levels in fibromyalgia patients

Substance-P is found at an elevated level in the cerebrospinal fluid of fibromyalgia (FM) patients. Treatment with tropisetron leads in a subgroup of FM patients to pain reduction. The question arises of whether the substance P level in the serum can be changed by tropisetron treatment.

Twenty patients with FM diagnosed according to the ACR criteria were treated for 5 days with a 5 mg tropisetron intravenous (i.v.) bolus injection daily. Before the first injection, 3 h later, and before and 3 h after the last injection, the serum levels of P-substance were determined. The determination of this substance was carried out by means of an immunoassay from Assay Design Biotrend, Cologne.

To evaluate the success of the tropisetron treatment, patients made a global assessment as ‘clearly better’, ‘better’, ‘unchanged’, or ‘poor’. Patients who answered ‘clearly better’ and ‘better’ were regarded as responders. Of the 20 patients, ten reported a good or very good influence on their pain (responders).

In these responders, the means of the serum substance-P levels were elevated in comparison with the non-responders, though the difference was not significant. In responders, the 5-HT3 receptor antagonist tropisetron produced a significant decrease in the serum substance P levels, while this did not occur in the non-responders.

Substance P Improves Learning and Memory

It 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. Moreover, injection of substance-P in parts of the brain that control motivation and reward facilitated learning and memory in rats. 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.

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  • Ablin JN, Buskila D. Maturitas. 2013 Aug;75(4):335-40. Fibromyalgia syndrome–novel therapeutic targets.
  • Bjersing JL, et al. Arthritis research & therapy. 2012 Jul 9;14(4):R162. Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides.
  • Substance P’s Role in Fibromyalgia – Verywell Health by Adriene Dellwo
  • Bokarewa MI, et al. Mediators of inflammation. 2014;2014:627041. Smoking is associated with reduced leptin and neuropeptide Y levels and higher pain experience in patients with fibromyalgia.

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