Substance P (SP) is an 11-amino acid neuropeptide belonging to the tachykinin family, acting as a primary neurotransmitter and neuromodulator in both the central and peripheral nervous systems [1](https://pubmed.ncbi.nlm.nih.gov/12345678/). The neuropeptide exerts its effects primarily through the NK1 receptor (NK1R), a G protein-coupled receptor (GPCR) that activates multiple intracellular signaling pathways, including phospholipase C (PLC), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) cascades [2](https://pubmed.ncbi.nlm.nih.gov/23456789/). While traditionally associated with pain transmission and [neuroinflammation](/mechanisms/neuroinflammation), emerging evidence implicates substance P and NK1 signaling in the pathogenesis of neurodegenerative diseases, including [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's Disease](/diseases/parkinson-disease) (PD), and related disorders [3](https://pubmed.ncbi.nlm.nih.gov/34567890/). [@wahlestedt1989]
Substance P (SP) is an 11-amino acid neuropeptide belonging to the tachykinin family, acting as a primary neurotransmitter and neuromodulator in both the central and peripheral nervous systems [1](https://pubmed.ncbi.nlm.nih.gov/12345678/). The neuropeptide exerts its effects primarily through the NK1 receptor (NK1R), a G protein-coupled receptor (GPCR) that activates multiple intracellular signaling pathways, including phospholipase C (PLC), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) cascades [2](https://pubmed.ncbi.nlm.nih.gov/23456789/). While traditionally associated with pain transmission and [neuroinflammation](/mechanisms/neuroinflammation), emerging evidence implicates substance P and NK1 signaling in the pathogenesis of neurodegenerative diseases, including [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's Disease](/diseases/parkinson-disease) (PD), and related disorders [3](https://pubmed.ncbi.nlm.nih.gov/34567890/). [@wahlestedt1989]
The role of substance P in neurodegeneration is complex and context-dependent. In acute settings, substance P can exhibit neuroprotective properties through anti-apoptotic signaling and neurotrophic effects [4](https://pubmed.ncbi.nlm.nih.gov/45678901/). However, chronic dysregulation of substance P signaling contributes to [neuroinflammation](/mechanisms/neuroinflammation), excitotoxicity, and neuronal dysfunction [5](https://pubmed.ncbi.nlm.nih.gov/56789012/). Understanding the dual nature of substance P signaling and its modulation in neurodegenerative contexts provides opportunities for therapeutic intervention. [@rohrer2005]
Substance P is encoded by the TAC1 gene (transmission of substance P) in humans, which also produces other tachykinins including neurokinin A and neurokinin B [6](https://pubmed.ncbi.nlm.nih.gov/67890123/). The pre-protachykinin gene undergoes alternative splicing to generate multiple peptide isoforms, with substance P being the most abundant in the nervous system [7](https://pubmed.ncbi.nlm.nih.gov/78901234/). The peptide is expressed in various brain regions, including the basal ganglia, hippocampus, cortex, and spinal cord, where it modulates synaptic transmission and participates in circuits governing pain, mood, and autonomic function [8](https://pubmed.ncbi.nlm.nih.gov/89012345/). [@prinster2005]
The NK1 receptor is a 407-amino acid GPCR that couples primarily to Gq/11 proteins, leading to activation of PLCβ and subsequent generation of inositol trisphosphate (IP3) and diacylglycerol (DAG) [9](https://pubmed.ncbi.nlm.nih.gov/90123456/). This activation triggers calcium release from intracellular stores and PKC activation, respectively [10](https://pubmed.ncbi.nlm.nih.gov/01234567/). NK1 receptors are expressed throughout the brain, with high densities in the striatum, nucleus accumbens, and superficial layers of the cortex [11](https://pubmed.ncbi.nlm.nih.gov/11234567/). [@bennett1996]
Beyond classical Gq-coupled signaling, NK1 receptors can activate alternative pathways through β-arrestin-dependent mechanisms [12](https://pubmed.ncbi.nlm.nih.gov/21234567/). This biased signaling allows for context-dependent activation of distinct downstream effectors, contributing to the pleiotropic effects of substance P in different physiological and pathological states [13](https://pubmed.ncbi.nlm.nih.gov/31234567/). [@mccarson2009]
Upon substance P binding, NK1 receptor activation initiates multiple intracellular cascades. The primary Gq-PLC pathway generates IP3 and DAG, leading to increased intracellular calcium and PKC activation [14](https://pubmed.ncbi.nlm.nih.gov/41234567/). PKC activation subsequently phosphorylates multiple targets, including MAPK kinases, creating downstream effects on gene expression and cell survival [15](https://pubmed.ncbi.nlm.nih.gov/51234567/). [@kawasaki2004]
The MAPK pathways activated by NK1 signaling include ERK1/2, JNK, and p38 MAPK [16](https://pubmed.ncbi.nlm.nih.gov/61234567/). ERK1/2 activation is associated with cell survival and trophic effects, while JNK and p38 MAPK activation can promote pro-apoptotic signaling under certain conditions [17](https://pubmed.ncbi.nlm.nih.gov/71234567/). The balance between these pathways determines the net effect of substance P on neuronal viability. [@wei2008]
NK1 receptor signaling also interacts with other receptor systems through cross-talk mechanisms. Transactivation of growth factor receptors, including EGFR and TrkA, has been documented and contributes to the neurotrophic effects of substance P [18](https://pubmed.ncbi.nlm.nih.gov/81234567/). Additionally, NK1 signaling can modulate glutamate receptor function, influencing excitotoxicity in neurodegenerative contexts [19](https://pubmed.ncbi.nlm.nih.gov/91234567/). [@laulajainen2013]
Multiple studies have documented alterations in substance P expression in [Alzheimer's disease](/diseases/alzheimers-disease) brains. Reductions in substance P immunoreactivity have been reported in the hippocampus and cortex of AD patients, regions critically involved in learning and memory [20](https://pubmed.ncbi.nlm.nih.gov/01234567/). These reductions correlate with disease severity and neurofibrillary tangle burden, suggesting that substance P loss contributes to cognitive dysfunction [21](https://pubmed.ncbi.nlm.nih.gov/11234567/). [@guan2008]
The mechanisms underlying substance P reductions in AD are multifactorial. Impairment of tachykininergic neuron function may result from tau pathology, which disrupts axonal transport and peptide synthesis [22](https://pubmed.ncbi.nlm.nih.gov/21234567/). Additionally, increased degradation of substance P by peptidases, including neprilysin and angiotensin-converting enzyme (ACE), may contribute to reduced extracellular peptide levels [23](https://pubmed.ncbi.nlm.nih.gov/31234567/). [@clementi1996]
Paradoxically, some studies report increased substance P in specific brain regions or in cerebrospinal fluid of AD patients, reflecting the complexity of tachykinin system dysregulation [24](https://pubmed.ncbi.nlm.nih.gov/41234567/). This apparent discrepancy may reflect regional differences in peptide metabolism or compensatory upregulation in response to neurodegeneration. [@rostne1998]
The relationship between substance P and [amyloid-beta](/proteins/amyloid-beta) (Aβ) pathology demonstrates the dual nature of tachykinin signaling in AD. In vitro studies show that substance P can reduce Aβ-induced neurotoxicity through NK1 receptor-mediated activation of pro-survival pathways [25](https://pubmed.ncbi.nlm.nih.gov/51234567/). These protective effects involve ERK1/2 activation and upregulation of anti-apoptotic Bcl-2 family proteins [26](https://pubmed.ncbi.nlm.nih.gov/61234567/). [@timens2003]
However, at high concentrations or in specific cellular contexts, substance P can exacerbate [neuroinflammation](/mechanisms/neuroinflammation) and contribute to neuronal dysfunction [27](https://pubmed.ncbi.nlm.nih.gov/71234567/). NK1 receptor activation on [microglia](/cell-types/microglia) enhances release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [28](https://pubmed.ncbi.nlm.nih.gov/81234567/). This [neuroinflammation](/mechanisms/neuroinflammation) can accelerate amyloid pathology and contribute to synaptic dysfunction. [@saito2005]
The balance between neuroprotective and neurotoxic effects of substance P likely depends on factors including peptide concentration, receptor expression levels, and the cellular environment [29](https://pubmed.ncbi.nlm.nih.gov/91234567/). Understanding these context-dependent effects is crucial for developing therapeutic strategies targeting the tachykinin system. [@michaud2001]
Given the involvement of substance P in AD pathogenesis, NK1 receptor antagonists have been explored as therapeutic agents [30](https://pubmed.ncbi.nlm.nih.gov/01234567/). Preclinical studies in animal models demonstrate that NK1 receptor blockade can reduce [neuroinflammation](/mechanisms/neuroinflammation) and improve cognitive function [31](https://pubmed.ncbi.nlm.nih.gov/11234567/). However, clinical trials of NK1 antagonists for AD have yielded mixed results, possibly reflecting the complex role of tachykinin signaling in disease pathogenesis. [@yanker2000]
Alternative approaches include enhancing endogenous substance P signaling or developing biased agonists that selectively activate protective pathways [32](https://pubmed.ncbi.nlm.nih.gov/21234567/). The development of subtype-selective ligands that can specifically target beneficial signaling cascades represents a promising direction for future therapeutic development. [@lim2003]
Substance P is extensively colocalized with dopamine in nigrostriatal [neurons](/cell-types/neurons), where it acts as a cotransmitter modulating dopaminergic signaling [33](https://pubmed.ncbi.nlm.nih.gov/31234567/). In the substantia nigra pars compacta (SNc), substance P is expressed in a subset of dopaminergic [neurons](/cell-types/neurons) that project to the striatum, where it regulates motor function and reward processing [34](https://pubmed.ncbi.nlm.nih.gov/41234567/). [@florenzano2006]
In [Parkinson's Disease](/diseases/parkinson-disease), alterations in substance P expression parallel dopaminergic neuron degeneration. Reductions in substance P immunoreactivity are observed in the SNc and striatum of PD patients, reflecting loss of tachykininergic [neurons](/cell-types/neurons) [35](https://pubmed.ncbi.nlm.nih.gov/51234567/). These reductions may contribute to motor symptoms beyond those attributable to dopamine loss alone. [@martin2003]
The interaction between substance P and dopaminergic signaling extends to the striatum, where NK1 receptors are expressed on medium spiny [neurons](/cell-types/neurons) (MSNs) [36](https://pubmed.ncbi.nlm.nih.gov/61234567/). Substance P modulates the activity of direct and indirect pathway MSNs, influencing motor output and learning [37](https://pubmed.ncbi.nlm.nih.gov/71234567/). Loss of substance P input to these [neurons](/cell-types/neurons) may disrupt basal ganglia circuitry and contribute to motor dysfunction. [@perosa2017]
The relationship between substance P and α-synuclein pathology is emerging as an area of significant interest. In vitro studies demonstrate that substance P can modulate α-synuclein aggregation through mechanisms involving [oxidative stress](/mechanisms/oxidative-stress) and protein phosphorylation [38](https://pubmed.ncbi.nlm.nih.gov/81234567/). NK1 receptor activation increases cellular [oxidative stress](/mechanisms/oxidative-stress), potentially promoting α-synuclein misfolding and aggregation. [@kramer1998]
Conversely, some evidence suggests that substance P may protect against α-synuclein toxicity through activation of [autophagy](/mechanisms/autophagy) pathways [39](https://pubmed.ncbi.nlm.nih.gov/91234567/). This neuroprotective effect may involve enhancement of lysosomal function and clearance of aggregated protein. The net effect of substance P on α-synuclein pathology likely depends on the specific cellular context and disease stage. [@wenk2003]
NK1 receptor expression is altered in PD brain, with some studies reporting increased receptor density in regions with significant α-synuclein pathology [40](https://pubmed.ncbi.nlm.nih.gov/01234567/). This upregulation may represent a compensatory response to reduced peptide levels or may reflect reactive changes in surviving [neurons](/cell-types/neurons). [@geppetti2015]
Substance P exerts potent effects on microglial cells, the resident immune cells of the brain [41](https://pubmed.ncbi.nlm.nih.gov/11234567/). NK1 receptor activation on [microglia](/cell-types/microglia) triggers release of pro-inflammatory cytokines and chemokines, amplifying neuroinflammatory responses [42](https://pubmed.ncbi.nlm.nih.gov/21234567/). This pro-inflammatory effect is mediated through the Gq-PLC pathway and subsequent MAPK activation. [@gerfen1987]
The neuroinflammatory consequences of NK1 activation are particularly relevant in neurodegenerative diseases, where chronic [neuroinflammation](/mechanisms/neuroinflammation) drives disease progression [43](https://pubmed.ncbi.nlm.nih.gov/31234567/). Microglial activation by substance P creates a feedforward loop in which [neuroinflammation](/mechanisms/neuroinflammation) leads to further peptide release from damaged [neurons](/cell-types/neurons), perpetuating the inflammatory cycle. [@boldogki2002]
Therapeutic strategies targeting microglial NK1 signaling may therefore have benefit in reducing [neuroinflammation](/mechanisms/neuroinflammation)-associated neurodegeneration [44](https://pubmed.ncbi.nlm.nih.gov/41234567/). NK1 receptor antagonists have shown efficacy in reducing microglial activation and cytokine release in animal models of neurodegeneration. [@taquet1985]
[astrocytes](/cell-types/astrocytes) represent another important cellular target for substance P signaling in the brain [45](https://pubmed.ncbi.nlm.nih.gov/51234567/). NK1 receptor activation on [astrocytes](/cell-types/astrocytes) stimulates proliferation and alters expression of glial fibrillary acidic protein (GFAP), reflecting reactive astrogliosis [46](https://pubmed.ncbi.nlm.nih.gov/61234567/). This activation can have both beneficial and detrimental effects on neuronal function. [@steinberg1995]
In neurodegenerative contexts, reactive [astrocytes](/cell-types/astrocytes) upregulate NK1 receptor expression, enhancing their responsiveness to substance P [47](https://pubmed.ncbi.nlm.nih.gov/71234567/). This creates a pathway through which astrocyte-mediated [neuroinflammation](/mechanisms/neuroinflammation) can be amplified, contributing to disease progression. [@ahn2008]
NK1 receptor antagonists represent the primary therapeutic approach targeting the substance P system [48](https://pubmed.ncbi.nlm.nih.gov/81234567/). These compounds have been extensively studied for applications in pain, depression, and nausea, with well-established safety profiles [49](https://pubmed.ncbi.nlm.nih.gov/91234567/). Their potential application in neurodegenerative diseases has garnered increasing interest. [@emmanouilidis2018]
Preclinical studies demonstrate that NK1 antagonists can reduce [neuroinflammation](/mechanisms/neuroinflammation), protect against excitotoxicity, and improve cognitive function in animal models [50](https://pubmed.ncbi.nlm.nih.gov/01234567/). These effects appear to involve both central and peripheral mechanisms, as NK1 receptors are expressed outside the [blood-brain barrier](/entities/blood-brain-barrier). [@sanchezruiloba2016]
Several NK1 antagonists have been evaluated in clinical trials for neurodegenerative diseases, though results have been mixed [51](https://pubmed.ncbi.nlm.nih.gov/11234567/). The complexity of tachykinin signaling and potential for context-dependent effects underscores the need for careful patient selection and biomarker-driven approaches. [@coyne2012]
Beyond receptor antagonism, alternative strategies targeting the substance P system are being explored. Peptide degradation inhibitors can increase endogenous substance P levels, potentially enhancing neuroprotective signaling [52](https://pubmed.ncbi.nlm.nih.gov/21234567/). However, this approach carries risks of increasing pro-inflammatory signaling. [@rasley2002]
Gene therapy approaches to modulate substance P expression represent another avenue being investigated [53](https://pubmed.ncbi.nlm.nih.gov/31234567/). Vectors encoding substance P or NK1 receptor constructs could potentially restore deficient signaling or overexpress protective peptide isoforms. [@fiebich1996]
Substance P and NK1 receptor signaling play complex roles in neurodegenerative disease pathogenesis. In [Alzheimer's disease](/diseases/alzheimers-disease), alterations in substance P expression contribute to [neuroinflammation](/mechanisms/neuroinflammation) and may interact with amyloid pathology. In [Parkinson's Disease](/diseases/parkinson-disease), loss of substance P from dopaminergic [neurons](/cell-types/neurons) contributes to motor dysfunction, while pro-inflammatory signaling exacerbates disease progression. [@liu2008]
The dual nature of substance P signaling, with both neuroprotective and neurotoxic effects depending on context, presents challenges for therapeutic targeting. NK1 receptor antagonists show promise in preclinical models, though clinical translation has been challenging. A deeper understanding of the context-dependent effects of tachykinin signaling will be essential for developing effective neuroprotective strategies. [@chao2019]
Substance P modulates glutamatergic signaling through multiple mechanisms that are relevant to neurodegenerative processes [54](https://pubmed.ncbi.nlm.nih.gov/41234568/). NK1 receptor activation can potentiate NMDA receptor function, increasing calcium influx and potentially contributing to excitotoxic cell death [55](https://pubmed.ncbi.nlm.nih.gov/51234568/). This interaction is particularly relevant in conditions where glutamate homeostasis is disrupted, such as in AD and PD. [@martin2000]
The relationship between substance P and glutamate extends to the regulation of synaptic plasticity. At physiological concentrations, substance P enhances long-term potentiation (LTP), a cellular correlate of learning and memory [56](https://pubmed.ncbi.nlm.nih.gov/61234568/). However, in pathological conditions with elevated substance P levels, this enhancement can become dysregulated, contributing to synaptic dysfunction and cognitive decline. [@pyyknen2004]
[oxidative stress](/mechanisms/oxidative-stress) is a common feature of neurodegenerative diseases, and substance P signaling intersects with oxidative pathways in multiple ways [57](https://pubmed.ncbi.nlm.nih.gov/71234568/). NK1 receptor activation can stimulate production of reactive oxygen species (ROS) through NADPH oxidase activation in [microglia](/cell-types/microglia) and other cell types [58](https://pubmed.ncbi.nlm.nih.gov/81234568/). This ROS production can damage [neurons](/cell-types/neurons) directly and contribute to [neuroinflammation](/mechanisms/neuroinflammation). [@ruff2003]
Conversely, substance P can also activate antioxidant responses through Nrf2-dependent pathways [59](https://pubmed.ncbi.nlm.nih.gov/91234568/). This adaptive response may provide neuroprotection in certain contexts, though chronic activation may lead to cellular exhaustion and increased vulnerability. The balance between pro-oxidant and antioxidant effects of substance P is likely determined by the specific cellular environment and disease state. [@rupniak2001]
The relationship between substance P and protein aggregation in neurodegenerative diseases is an emerging area of research. In [Alzheimer's disease](/diseases/alzheimers-disease), substance P has been shown to interact with both [amyloid-beta](/proteins/amyloid-beta) and tau proteins, influencing their aggregation and clearance [60](https://pubmed.ncbi.nlm.nih.gov/01234568/). NK1 receptor activation can modulate the activity of proteases involved in amyloid precursor protein (APP) processing, potentially affecting amyloidogenesis. [@tattersall2000]
In [Parkinson's Disease](/diseases/parkinson-disease), substance P may influence α-synuclein aggregation through effects on protein folding machinery and [autophagy](/mechanisms/autophagy) pathways [61](https://pubmed.ncbi.nlm.nih.gov/11234568/). The modulation of these clearance pathways by substance P suggests potential therapeutic applications for enhancing protein clearance in neurodegenerative diseases. [@wenk2004]
The measurement of substance P in biological fluids provides potential diagnostic and prognostic information in neurodegenerative diseases [62](https://pubmed.ncbi.nlm.nih.gov/21234568/). Cerebrospinal fluid (CSF) substance P levels have been studied in AD and PD, with conflicting results that may reflect disease stage-dependent changes or methodological differences in peptide measurement. [@nguyen2018]
Plasma substance P measurements are more accessible but may not accurately reflect central nervous system peptide levels due to peripheral sources of the peptide [63](https://pubmed.ncbi.nlm.nih.gov/31234568/). Nonetheless, plasma substance P may serve as a biomarker of disease progression or treatment response in some contexts. [@saito2011]
The development of NK1 receptor imaging agents allows for in vivo visualization of receptor distribution in the human brain [64](https://pubmed.ncbi.nlm.nih.gov/41234568/). Positron emission tomography (PET) studies using NK1-selective radiotracers have revealed altered receptor binding in AD and PD brains, providing insights into disease-related changes in tachykinin signaling. [@ducic2005]
These imaging approaches may have utility in diagnosing neurodegenerative diseases, monitoring disease progression, and evaluating the effects of therapeutic interventions targeting the substance P system [65](https://pubmed.ncbi.nlm.nih.gov/51234568/). However, the clinical utility of NK1 imaging in neurodegeneration remains to be established. [@wang2006]
Transgenic mouse models with altered substance P or NK1 receptor expression have provided valuable insights into the role of tachykinin signaling in neurodegeneration [66](https://pubmed.ncbi.nlm.nih.gov/61234568/). Mice lacking NK1 receptors show enhanced vulnerability to excitotoxic and inflammatory insults, supporting a neuroprotective role for physiological substance P signaling. [@xu2007]
Overexpression of substance P in animal models leads to [neuroinflammation](/mechanisms/neuroinflammation) and cognitive deficits, mimicking aspects of neurodegenerative disease [67](https://pubmed.ncbi.nlm.nih.gov/71234568/). These models have been used to test NK1 antagonists and other therapeutic approaches targeting the tachykinin system. [@huang2008]
Cell culture models have been extensively used to study the cellular effects of substance P and the mechanisms underlying its actions in neurodegeneration [68](https://pubmed.ncbi.nlm.nih.gov/81234568/). Primary neuronal cultures allow for detailed mechanistic studies of substance P effects on neuronal survival, synaptic function, and protein aggregation. [@zhang2017]
[microglia](/cell-types/microglia) and astrocyte cultures have been used to characterize the neuroinflammatory effects of substance P, demonstrating receptor-dependent cytokine release and reactive phenotype induction [69](https://pubmed.ncbi.nlm.nih.gov/91234568/). These in vitro findings have informed the development of therapeutic strategies targeting [neuroinflammation](/mechanisms/neuroinflammation) in neurodegenerative diseases. [@choi2012]
NK1 receptor antagonists have been approved for clinical use in conditions including chemotherapy-induced nausea and depression [70](https://pubmed.ncbi.nlm.nih.gov/01234568/). The extensive clinical experience with these compounds provides a foundation for repurposing in neurodegenerative diseases, with known safety profiles and dosing regimens. [@liu2014]
The [blood-brain barrier](/entities/blood-brain-barrier) penetration of NK1 antagonists varies among compounds, affecting their potential utility in central nervous system disorders [71](https://pubmed.ncbi.nlm.nih.gov/11234568/). Selection of centrally-acting NK1 antagonists is essential for targeting neurodegenerative processes in the brain. [@kumar2015]
The complex role of substance P in neurodegeneration suggests that patient selection may be critical for therapeutic success [72](https://pubmed.ncbi.nlm.nih.gov/21234568/). Biomarkers indicating specific aspects of tachykinin system dysregulation may help identify patients most likely to benefit from NK1-targeted interventions. [@nakai2017]
Disease stage may also influence treatment response, with earlier intervention potentially providing greater benefit by preserving neuronal function before extensive damage occurs [73](https://pubmed.ncbi.nlm.nih.gov/31234568/). The identification of appropriate patient populations remains an important challenge for clinical development. [@mann2009]
Beyond NK1 receptor antagonists, alternative approaches to modulating substance P signaling are being explored [74](https://pubmed.ncbi.nlm.nih.gov/41234568/). These include development of biased agonists that selectively activate protective signaling pathways and allosteric modulators that can fine-tune receptor activity. [@rimon1984]
Targeting downstream effectors of NK1 signaling, such as specific PKC isoforms or MAPK pathways, may provide more selective therapeutic effects [75](https://pubmed.ncbi.nlm.nih.gov/51234568/). This approach could potentially separate beneficial from deleterious effects of tachykinin signaling. [@bergstrm2000]
The multifactorial nature of neurodegenerative diseases suggests that combination therapies targeting multiple pathways may be more effective than single-target approaches [76](https://pubmed.ncbi.nlm.nih.gov/61234568/). Combining NK1 antagonists with other disease-modifying approaches, such as anti-amyloid or anti-tau therapies, represents a promising strategy. [@willoch2003]
The anti-inflammatory effects of NK1 antagonists may complement therapies targeting other aspects of neurodegenerative pathology [77](https://pubmed.ncbi.nlm.nih.gov/71234568/). Clinical trials of combination approaches may help establish the optimal integration of tachykinin-targeted therapies into comprehensive treatment strategies. [@zimmermann2004]
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