NK1 receptor antagonists for depression: Why a validated concept was abandoned

Rupniak, N. M. J.; Kramer, Mark S.

doi:10.1016/j.jad.2017.07.042

Cited by 41 publications

(30 citation statements)

References 26 publications

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“…This failure could be due, at least to some extent, to a misconception of what characterizes pain as a chronic disease. Both preclinical and clinical evidence support the involvement of tachykinins and NK1 and NK2 receptors in the neurobiology of depression and anxiety disorders, key features of suffering during chronic pain states (Ebner et al 2009; Bardelli et al 2013; Catena-Dell’Osso et al 2013; Kormos and Gaszner 2013; Rupniak and Kramer 2017). …”

Section: Substance P a Member Of The Tachykinin Peptide Familymentioning

confidence: 93%

Substance P and pain chronicity

2018

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Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

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Section: Substance P a Member Of The Tachykinin Peptide Familymentioning

confidence: 93%

Substance P and pain chronicity

2018

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“…If so, the critical differences in pain pathways between rodents and humans need to be studied. Hill (2000) suggested that the analgesic effects of NK1R antagonists could be due to their supraspinal effects on stress (Rupniak and Kramer, 2017). Indeed, stress induces hyperalgesia in rats with latent sensitization (Chen et al, 2018b;Rivat et al, 2007).…”

Section: Failure Of Nk1r Antagonists In Clinical Trialsmentioning

confidence: 99%

“…NK1R antagonists have important effects in the brain (Rupniak and Kramer, 2017) that might counteract their effects on the spinal cord. Finally, the discovery of biased agonism (Simmons, 2005;Smith et al, 2018;Urban et al, 2007) shows that the properties of one agonist cannot be extended to other agonists at the same receptor.…”

Section: Failure Of Nk1r Antagonists In Clinical Trialsmentioning

confidence: 99%

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain

Chen

Marvizón

2020

Preprint

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Latent sensitization is a model of chronic pain in which a persistent state of pain hypersensitivity is suppressed by opioid receptors, as evidenced by the ability of opioid antagonists to induce a period of mechanical allodynia. Our objective was to determine if substance P and its neurokinin 1 receptor (NK1R) mediate the maintenance of latent sensitization. Latent sensitization was induced by injecting rats in the hindpaw with complete Freund's adjuvant (CFA), or by spared nerve injury (SNI). When responses to von Frey filaments returned to baseline (day 28), the rats were injected intrathecally with saline or the NK1R antagonist RP67580, followed 15 min later by intrathecal naltrexone. In both pain models, the saline-injected rats developed allodynia for 2 h after naltrexone, but not the RP67580injected rats. Saline or RP67580 were injected daily for two more days. Five days later (day 35), naltrexone was injected intrathecally. Again, the saline-injected rats, but not the RP67580injected rats, developed allodynia in response to naltrexone. To determine if there is sustained activation of NK1Rs during latent sensitization, NK1R internalization was measured in lamina I neurons in rats injected in the paw with saline or CFA, and then injected intrathecally with saline or naltrexone on day 28. The rats injected with CFA had a small amount of NK1R internalization that was significantly higher than in the saline-injected rats. Naltrexone increased NK1R internalization in the CFA-injected rats but nor in the saline-injected rats. Therefore, sustained activation of NK1Rs maintains pain hypersensitivity during latent sensitization.

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“…Since the drug approval of the selective NK-1 receptor antagonist aprepitant as an antiemetic agent, no further indication areas were approved by US-American and European regulatory agencies due to failures of NK-1 receptor antagonists in phase-III clinical trials [4]. The discrepancy between these failures and promising preclinical studies leads to the assumption that the roles of the tachykinins are not fully understood until now [5]. This lack of knowledge may be based on the high variability of SP blood levels caused by distinct analytical techniques and sample preparation methods [6][7][8].…”

Section: Rpkpqqffglm-nh2mentioning

confidence: 99%

A design of experiments concept for the minimization of nonspecific peptide adsorption in the mass spectrometric determination of substance P and related hemokinin‐1

Feickert

Burckhardt

2019

J of Separation Science

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Substance P and hemokinin‐1 were predominantly examined by immunoassays with their limitation to differentiate appropriately between both peptides. The use of liquid chromatography coupled with tandem mass spectrometry is a promising, highly selective alternative. Adsorption processes have been identified in preliminary experiments to play a crucial role in the loss of mass spectrometry intensity of both peptides. Therefore, a design of experiments concept was created to minimize nonspecific peptide adsorption. For this purpose, the most critical influencing parameters—(1) the composition of the injection solvent as well as (2) the most suitable container material—were systematically and concordantly investigated. The addition of modifiers, such as formic acid, dimethyl sulfoxide, and organic solvents, to the injection solvent led to a substantial gain of intensity of substance P and hemokinin‐1 compared to the start gradient as an injection solvent. Furthermore, the systematic investigation underlined the high impact of the container material, demonstrating polypropylene as the most favorable material. A conjoint injection solvent optimum was found to determine both peptides simultaneously by the conduction of a sweet‐spot analysis. The experimental design substantially reduced nonspecific peptide adsorption and enabled the simultaneous and selective determination of endogenous substance P and hemokinin‐1 plasma levels.

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NK1 receptor antagonists for depression: Why a validated concept was abandoned

Cited by 41 publications

References 26 publications

Substance P and pain chronicity

Substance P and pain chronicity

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain

A design of experiments concept for the minimization of nonspecific peptide adsorption in the mass spectrometric determination of substance P and related hemokinin‐1

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