Substance P

Substance P (SP) is an 11-amino acid neuropeptide belonging to the tachykinin family, encoded by the TAC1 gene and acting primarily through the neurokinin-1 (NK1) receptor. It serves as a key neurotransmitter in pain transmission, a mediator of neurogenic inflammation, and a critical regulator of immune function and tissue repair. SP is synthesized in sensory neurons and released from C-fibers in response to noxious stimuli, playing multifaceted roles in nociception, cardiovascular regulation, wound healing, and immune modulation.

Pain Transmission and Nociception

Substance P functions as a primary neurotransmitter in nociceptive pathways, being synthesized in small-caliber afferent fibers and released into the spinal cord after noxious stimulation where it excites nociceptive dorsal horn neurons ^[1][2]. It is abundantly expressed in the superficial layers of the spinal cord dorsal horn, with its action mediated through the NK-1 receptor ^[3]. Following stimulation of nociceptive afferents, SP is released and transmission is primarily mediated by tachykinin NK1 receptors concentrated in neurons of lamina I of the superficial dorsal horn ^[4].

Neurogenic Inflammation and Central Sensitization

SP plays a crucial role in central sensitization, the process by which excitability of nociceptive dorsal horn neurons is enhanced after tissue injury ^[3][5]. Activation of NMDA and neurokinin receptors in dorsal horn neurons enhances central summation effects, with SP synthesis and release induced by peripheral noxious stimuli contributing to central sensitization ^[3]. Nerve fibers enhance wound healing by promoting initial inflammation via the release of neuropeptides such as SP, initiating a neurogenic inflammatory response in the early stages of healing ^[6].

Wound Healing and Tissue Repair

SP exhibits potent wound healing activity, produced by both neuronal and immune cells during tissue injury ^[7][8]. It accelerates diabetic wound healing through modulating inflammatory responses, notably the activation of NF-κB and inflammatory cell density ^[9]. SP promotes angiogenesis by modulating levels of transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and interleukin 10 (IL-10) during wound healing ^[9]. Topical application of exogenous SP enhanced wound healing significantly in diabetic rat wound models, with SP treatment significantly increasing wound closure, levels of interleukin-10, and expressions of VEGF ^[10][11].

Immune System Modulation

SP acts as a proinflammatory mediator through NK1R signaling, activating immune cells including macrophages, neutrophils, and dendritic cells ^[7]. SP induces HO-1 expression in macrophages promoting switch towards M2-like phenotype from both resting and M1 macrophages, playing a role in the resolution of inflammation ^[12]. SP-NK1R interaction regulates immune cell function, with IL-23 regulating SP levels in mouse macrophages and NK1R expression upregulated by both Th1 (IFN-γ) and Th2 (IL-4) cytokines ^[7][13].

Cardiovascular Effects

SP functions as a potent vasodilator acting through endothelial NK1 receptors ^[14]. Blockade of endogenous NK1 receptors reduced resting muscle sympathetic activity by 38%, reduced systemic vascular resistance by 25%, and increased cardiac index by 47%, suggesting SP exerts tonic enhancement of sympathetic outflow to cardiovascular structures ^[15]. SP is involved in the regulation of heart frequency, blood pressure, and vessel stretching, with microinjections in the nucleus tractus solitarius resulting in decreases of blood pressure and heart rate .

Therapeutic Applications

NK1 receptor antagonists (aprepitant, fosaprepitant, netupitant) are FDA-approved antiemetics highly effective for preventing chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting . SP combined with insulin-like growth factor-1 (IGF-1) promotes corneal epithelial wound healing, with clinical applications in treating persistent corneal epithelial defects associated with neurotrophic keratopathy ^[7]. SP actively regulates wound healing-related cells, exhibiting robust inflammatory properties, promoting cell proliferation and migration, and restoring activity of skin cells under diabetic conditions ^[9].

NK1 Receptor Antagonist Safety Profile

NK1 receptor antagonists have demonstrated favorable safety profiles in clinical trials. The antagonist L-759274 was generally safe and well-tolerated, with sexual side effects on par with placebo and low incidences of gastrointestinal effects . In clinical trials with aprepitant (MK-869), the side-effect profile was relatively innocuous, with indices for sexual side effects and gastrointestinal symptoms similar to those observed in the placebo group . Aprepitant and fosaprepitant are used safely as antiemetic agents for preventing nausea and vomiting associated with chemotherapy .

Clinical Trial Limitations

Despite identification of high affinity and selective SP (NK1) receptor antagonists and preclinical data supporting an analgesic profile, outcomes from clinical trials for pain management have been disappointing with no clear analgesic efficacy observed in various pain states ^[4]. Multiple NK1 antagonist compounds were developed up to Phase II clinical trials for neuropathic pain treatment but showed no significant effects . This represents a significant clinical translation gap between animal models and human pain treatment outcomes ^[5].

Endogenous Substance P Considerations

As an endogenous neuropeptide, SP is naturally present in the nervous and immune systems. SP levels decreased in diabetic wounds, and topical application of exogenous SP enhanced wound healing in diabetic models without reported adverse effects ^[10][11]. However, increased levels of SP are found in pathological conditions - elevated SP was detected in synovial fluid and serum of patients with rheumatoid arthritis, with NK-1R mRNA upregulated in RA synoviocytes, indicating SP's role in inflammatory disease ^[13].

Therapeutic Application Safety

While SP stimulates wound healing by regulating cytokine production and cell proliferation and migration, its therapeutic application is limited by low stability under biological conditions and oxidation during purification, formulation, and storage, prompting development of novel formulations such as SP gel and hydrogel-based delivery systems ^[6]. SP treatment in animal wound models has shown safety when applied topically once daily for extended periods (19 days) at 10^-6 M concentration in pluronic gel ^[10].

Contraindications and Precautions

Given SP's role as a proinflammatory mediator that activates immune cells and enhances inflammatory responses ^[7][13], caution should be exercised in conditions where excessive inflammation may be detrimental. SP's involvement in pain chronicity and central sensitization suggests that while it plays physiological roles in acute nociception, sustained elevation may contribute to chronic pain states ^[5]. The absence of clear analgesic efficacy from NK1 antagonists in human pain trials contrasts with preclinical expectations, highlighting the complexity of SP's role in human pain pathophysiology ^[4].