Review
The tachykinin NK1 receptor in the brain: pharmacology and putative functions

https://doi.org/10.1016/S0014-2999(99)00259-9Get rights and content

Abstract

After its discovery in 1931, substance P (SP) remained the only mammalian member of the family of tachykinin peptides for several decades. Tachykinins thus refer to peptides sharing the common C-terminal amino acid sequence Phe–X–Gly–Leu–Met·NH2. In recent years the family of mammalian tachykinins has grown with the isolation of two novel peptides from bovine and porcine central nervous system (CNS), neurokinin A and neurokinin B. In parallel with the identification of multiple endogenous tachykinins several classes of tachykinin receptors were discovered. The receptors described so far are named tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor, respectively. The present review focuses on the pharmacology and putative function of tachykinin NK1 receptors in brain. The natural ligand with the highest affinity for the tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the tachykinin NK1 receptor is the C-terminal hexapeptide. A rapid advance of knowledge was caused by development of non-peptidic tachykinin NK1 receptor antagonists. This area is under rapid development and a variety of different chemical classes of compounds are involved. Species-dependent affinities of tachykinin NK1 receptor antagonists reveal two clusters of compounds, targeting the tachykinin NK1 receptor subtype found in guinea pig, human or ferret or the one in rat or mouse, respectively. The most recently developed compounds are highly selective, enter the brain and are orally bioavailable. Distinct behavioural effects in experimental animals suggest the involvement of tachykinin NK1 receptors in nociceptive transmission, basal ganglia function or anxiety and depression. Recent clinical trials in man showed that tachykinin NK1 receptor antagonists are effective in treating depression and chemotherapy-induced emesis. Therefore, it is well possible that tachykinin NK1 receptor antagonists will be clinically used for treatment of specific CNS disorders within a short period of time.

Introduction

After its discovery in 1931, substance P (SP) remained the only mammalian member of the family of tachykinin peptides for several decades. Tachykinins thus refer to peptides sharing the common C-terminal amino acid sequence Phe–X–Gly–Leu–Met·NH2 (Table 1). In recent years the family of mammalian tachykinins has grown with the isolation of two novel peptides from bovine and porcine central nervous system (CNS), neurokinin A and neurokinin B (McLean, 1996). In parallel with the identification of multiple endogenous tachykinins several classes of tachykinin receptors were discovered. It has been observed that SP and the non-mammalian tachykinins eledoisin and kassinin exhibited different agonist potencies depending on the used bioassay system (McLean, 1996). Iversen et al. (see Lee et al., 1986; McLean, 1996), identified two distinct tachykinin potency profiles in smooth muscle preparations and proposed the existence of SP-P and SP-E receptors. Evidence for the existence of the two pharmacologically distinguishable sites was further provided by binding experiments with peptide radioligands (Beaujouan et al., 1986; Danks et al., 1986). With the discovery of a third binding site (Laufer et al., 1986) and the isolation of novel mammalian tachykinins, some by several groups in parallel, the nomenclature of tachykinins and their receptors became completely confusing. In 1984, at the tachykinin symposium in Montreal the following nomenclature was proposed (McLean, 1996). The endogenous mammalian tachykinins were designated as neurokinin A (previously also referred to as neurokinin α, neuromedin L or substance K) and neurokinin B (previously also named neurokinin β or neuromedin K). Furthermore, the receptors would be referred to as tachykinin NK1 receptor (previously SP-P), tachykinin NK2 receptor (previously SP-E, SP-K, NK-A) and NK3 (previously also SP-E, SP-N, NK-B). SP is the most potent tachykinin for the tachykinin NK1 receptor, whereas neurokinin A exhibits the highest affinity for the tachykinin NK2 receptor and neurokinin B for the tachykinin NK3 receptor, respectively. It has, however, to be pointed out clearly that all mammalian tachykinins have limited selectivity for a particular neurokinin receptor. Table 2 summarizes this limited selectivity. It is important to note that despite the early evidence for a cross-talk between different tachykinins at the different receptors, the tachykinin NK1 receptor was de facto considered to be the SP receptor and, in other words, SP to be the physiological ligand for the tachykinin NK1 receptor. In accordance, similar conclusions were applied to neurokinin A and the tachykinin NK2 receptor, and neurokinin B and the tachykinin NK3 receptor (Maggi and Schwartz, 1997). This dogma was so well established that homologous binding experiments using the `wrong' tachykinin were not performed on the cloned receptors until recently (Maggi and Schwartz, 1997). With this in mind, it seems extremely difficult to sort out a particular function for one of the tachykinin peptides. Thus, it seems more rational to focus on the distribution and pharmacology of particular tachykinin receptors. Due to the more abundant distribution of tachykinin NK1 receptors (Quartara and Maggi, 1998) and the variety of available synthetic agonists and antagonists for this tachykinin receptor (McLean, 1996; Maggi and Schwartz, 1997; Quartara and Maggi, 1997, Quartara and Maggi, 1998), this review predominantly describes tachykinin NK1 receptor pharmacology. The distribution and putative function of tachykinin NK1 receptors in the peripheral nervous system and in the gut has been recently discussed extensively in several reviews (McLean, 1996; Quartara and Maggi, 1997, Quartara and Maggi, 1998). The present review therefore focuses on the pharmacology and putative function of tachykinin NK1 receptors in the CNS.

Section snippets

Distribution of tachykinin NK1 receptors in the CNS

The distribution of tachykinin NK1 receptors in the mammalian CNS has been investigated by autoradiography (Dam and Quirion, 1986; Danks et al., 1986; Saffroy et al., 1988), by studying the expression of messenger ribonucleic acid (mRNA) encoding for the receptor (Sivam and Krause, 1992; Aubry et al., 1994; Whitty et al., 1995; Whitty et al., 1997) and by immunohistochemistry (Shigemoto et al., 1993). Basically, the different approaches revealed comparable results and have provided evidence for

Properties of the tachykinin NK1 receptor

The pharmacological criteria to define a tachykinin NK1 receptor originate from the analyses of the rank order of potencies of natural mammalian and non-mammalian tachykinins and their fragments on binding and various bioassays, preferably in vitro, but in some instances also in vivo (Maggi et al., 1987; Regoli et al., 1987, Regoli et al., 1988, Regoli et al., 1989; Regoli and Nantel, 1991; Quartara and Maggi, 1997). The tachykinin NK1 receptor has been cloned from several species including man

Ligands for the tachykinin NK1 receptor

The natural ligand with the highest affinity for the tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the tachykinin NK1 receptor is the C-terminal hexapeptide (see Table 1). As discussed above, neurokinin A and neurokinin B do possess considerable affinity for the tachykinin NK1 receptor as well. Therefore, synthesis of more selective ligands targeting one of the tachykinin receptor subtypes

Non-peptide tachykinin NK1 receptor antagonists

The story of non-peptide antagonists for the tachykinin receptors started in 1991, when several different groups almost at the same time reported compounds possessing tachykinin receptor-antagonistic properties (Maggi et al., 1993; Regoli et al., 1994). As this area is under rapid development and a variety of different chemical classes of compounds are involved, such substances may be classified by basic structures. Basically, the first of the antagonists were found by screening of chemical

Species-dependent affinities of tachykinin NK1 antagonists reveal two clusters of compounds

The cloned human and rat tachykinin NK1 receptors show about 95% homology, i.e. 21 out of 407 amino acid residues differ between these two species. The majority of these residues is localized at the C- and N-terminal ends of the receptor protein. When analyzing the transmembrane segments 1–7, only six amino acids differ between these two species. With one exception (266 in transmembrane segment 6, i.e., valine in rat and isoleucine in mouse) the mouse and rat tachykinin NK1 receptor have the

Signal transduction coupling of the tachykinin NK1 receptor

It is well established that the binding of tachykinin receptor agonists is regulated by guanine nucleotides indicating coupling to G-proteins (Guard and Watson, 1991). More recent findings from desoxyribonucleic acid cloning and functional expression experiments of all three tachykinin receptors provide clear evidence for this view (Macdonald and Boyd, 1989; Kwatra et al., 1993; Mochizuki et al., 1994; Macdonald et al., 1996). The stimulation of tachykinin NK1 receptors activates several second

Tachykinin NK1 receptors in the spinal cord and their involvement in nociception

Originally, the newly developed non-peptidic tachykinin NK1 receptor antagonists were tested for putative antinociceptive effects as SP has repeatedly been proposed as a `pain transmitter'. However, the situation turned out to be extremely complicated and the efficacy of different tachykinin NK1 receptor antagonists as antinociceptive compounds has been found to be poor in some instances. This review does not go into details of this complex issue, but refers to some recent reviews that

Tachykinin NK1 receptor agonists and behaviour

The abundant distribution of tachykinin NK1 receptors in brain is reflected by a wide variety of behavioural changes after central administration of SP or selective tachykinin NK1 receptor agonists. Locomotion, grooming, wet-dog shakes, hind paw tapping, in some instances species related, have been observed after central administration of tachykinin NK1 receptor agonists, probably related to the release of other transmitters such as dopamine, serotonin, or acetylcholine (Elliott and Iversen,

Conclusions from tachykinin NK1 receptor knockout mice

Investigation of behaviour of mice after targeted disruption of the gene for the tachykinin NK1 receptor revealed further insight into putative functions (De et al., 1998). Interestingly, in these mice the behavioural responses to acute nociceptive thermal, mechanical or chemical stimuli (hot plate, tail flick, tail pinch, and writhing test) appear to be normal. A minor effect (30% decrease of the behavioural response to the second phase of the formalin paw test) could be detected. This is in

Behavioural and other central effects of tachykinin NK1 receptor antagonists

An even more detailed picture of the putative physiological and pathophysiological roles of the tachykinin NK1 receptor in brain can be obtained from the experiments with tachykinin NK1 receptor antagonists. There have been several drawbacks of earlier compounds due to unspecific side effects, poor solubility and poor penetration into the CNS after systemic administration. However, the compounds developed more recently seem to be not only highly specific, but also penetrating the CNS and, as

Basal ganglia-related effects and mechanisms

The basal ganglia represent a brain area where high concentrations of both tachykinins and neurokinin receptors can be detected. As a result, many studies have been performed in this area and attempts were made to relate mechanisms involving tachykinins and tachykinin receptors to extrapyramidal motor diseases such as Parkinson's disease and Chorea Huntington. Interactions between the meso-striatal dopamine system and tachykinins have been observed with a number of interdisciplinary approaches.

Anxiety and depression

Recent studies with non-peptidic tachykinin NK1 receptor antagonists suggested a putative anxiolytic effect (Teixeira et al., 1996; File, 1997) although this could not be demonstrated earlier possibly due to the sedative and motor impairing effect of one of the early compounds (Zernig et al., 1992, Zernig et al., 1993; Saria et al., 1993). The recent data are compatible with the anxiogenic profile of centrally administered SP on the elevated plus maze (Elliott and Iversen, 1986). A significant

Emesis

Tachykinins are localized in the brainstem not only of rodents, but also in the ferret in areas that are assumed to be involved in nausea and emesis. Ferrets provide a useful experimental model for studying emesis induced by various agents. As ferrets express the human/guinea pig subtype of tachykinin NK1 receptors, proper compounds with tachykinin NK1 receptor antagonism have been studied in this model (Watson et al., 1995). Centrally acting (+)-2S,3S

Other effects of tachykinin NK1 receptor antagonists in brain

Few additional studies provide evidence for discrete functions in brain. Intracerebroventricular injection of RP 67580 attenuates some symptoms of the responses to morphine withdrawal in rats (Maldonado et al., 1993). Furthermore, tachykinin NK1 receptors are involved in stress-induced activation of ascending central pathways in the locus coeruleus (McLean et al., 1993). The involvement of tachykinins in central control of stress responses has been shown with tachykinin NK1 receptor antagonists

References (115)

  • P.J Elliott et al.

    Behavioural effects of tachykinins and related peptides

    Brain Res.

    (1986)
  • P.J Elliott et al.

    Modulation of the rat mesolimbic dopamine pathway by neurokinins

    Behav. Brain Res.

    (1992)
  • S.E File

    Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test

    Pharmacol. Biochem. Behav.

    (1997)
  • T.M Fong et al.

    Molecular basis for the species selectivity of the neurokinin-1 receptor antagonist CP-96345

    J. Biol. Chem.

    (1992)
  • T Futami et al.

    Expression of substance P receptor in the substantia nigra

    Brain Res. Mol. Brain Res.

    (1998)
  • M Garcia et al.

    Multiple mechanisms of arachidonic acid release in Chinese hamster ovary cells transfected with cDNA of substance P receptor

    Biochem. Pharmacol.

    (1994)
  • S Gonsalves et al.

    Broad spectrum antiemetic effects of CP-122,721, a tachykinin NK1 receptor antagonist, in ferrets

    Eur. J. Pharmacol.

    (1996)
  • V Gorbulev et al.

    Molecular cloning of substance P receptor cDNA from guinea-pig uterus

    Biochim. Biophys. Acta

    (1992)
  • S Guard et al.

    Tachykinin receptor types: classification and membrane signalling mechanisms

    Neurochem. Int.

    (1991)
  • M Herkenham

    Mismatches between neurotransmitter and receptor localizations in brain: observations and implications

    Neuroscience

    (1987)
  • R Hosoki et al.

    Pharmacological profiles of new orally active nonpeptide tachykinin NK1 receptor antagonists

    Eur. J. Pharmacol.

    (1998)
  • X.Y Hua et al.

    Capsaicin induced release of multiple tachykinins (substance P, neurokinin A and eledoisin-like material) from guinea-pig spinal cord and ureter

    Neuroscience

    (1986)
  • W Krase et al.

    Substance P is involved in the sensitization of the acoustic startle response by footshocks in rats

    Behav. Brain Res.

    (1994)
  • M.M Kwatra et al.

    The substance P receptor, which couples to Gq/11, is a substrate of beta-adrenergic receptor kinase 1 and 2

    J. Biol. Chem.

    (1993)
  • R Laufer et al.

    Characterization of a neurokinin B receptor site in rat brain using a highly selective radioligand

    J. Biol. Chem.

    (1986)
  • S Lavielle et al.

    Highly potent substance P antagonists substituted with beta-phenyl-or beta-benzyl-proline at position 10

    Eur. J. Pharmacol.

    (1994)
  • C.M Lee et al.

    Multiple tachykinin binding sites in peripheral tissues and in brain

    Eur. J. Pharmacol.

    (1986)
  • U Liminga et al.

    Intranigral stimulation of oral movements by [pro(9)] substance-P, a neurokinin-1 receptor agonist, is enhanced in chronically neuroleptic-treated rats

    Behav. Brain Res.

    (1993)
  • C.A Maggi

    Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity

    Pharmacol. Res.

    (1997)
  • C.A Maggi et al.

    The dual nature of the tachykinin NK1 receptor

    Trends Pharmacol. Sci.

    (1997)
  • C.A Maggi et al.

    Activity of spantide I and II at various tachykinin receptors and NK2 tachykinin receptor subtypes

    Eur. J. Pharmacol.

    (1991)
  • R Maldonado et al.

    RP 67580, a selective antagonist of neurokinin-1 receptors, modifies some of the naloxone-precipitated morphine withdrawal signs in rats

    Neurosci. Lett.

    (1993)
  • J Marksteiner et al.

    Differential increases of neurokinin B- and enkephalin-like immunoreactivities and their mRNAs after chronic haloperidol treatment in the rat

    Neurosci. Lett.

    (1992)
  • J Marksteiner et al.

    Increased synthesis of neurokinin B and enkephalin after chronic haloperidol treatment

    Regul. Pept.

    (1993)
  • Y Nakajima et al.

    Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells

    J. Biol. Chem.

    (1992)
  • L.A Phebus et al.

    The non-peptide NK1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs

    Life Sci.

    (1997)
  • C Polidori et al.

    Further evidence that central tachykinin NK1 receptors mediate the inhibitory effect of tachykinins on angiotensin-induced drinking in rats

    Peptides

    (1998)
  • L Quartara et al.

    The tachykinin NK1 receptor: Part I. ligands and mechanisms of cellular activation

    Neuropeptides

    (1997)
  • L Quartara et al.

    The tachykinin NK1 receptor: Part II. Distribution and pathophysiological roles

    Neuropeptides

    (1998)
  • V Radhakrishnan et al.

    The nonpeptide NK1 receptor antagonists LY303870 and LY306740 block the responses of spinal dorsal horn neurons to substance P and to peripheral noxious stimuli

    Neuroscience

    (1998)
  • D Regoli et al.

    New selective agonists for neurokinin receptors: pharmacological tools for receptor characterization

    Trends Pharmacol. Sci.

    (1988)
  • D Regoli et al.

    Pharmacological receptors for substance P and neurokinins

    Life Sci.

    (1987)
  • N.M Rupniak et al.

    In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists

    Eur. J. Pharmacol.

    (1997)
  • B.S Sachais et al.

    Molecular basis for the species selectivity of the substance P antagonist CP-96,345

    J. Biol. Chem.

    (1993)
  • M Saffroy et al.

    Localization of tachykinin binding sites (NK1, NK2, NK3 ligands) in the rat brain

    Peptides

    (1988)
  • A Saria et al.

    Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices

    Neurosci. Lett.

    (1986)
  • A Saria et al.

    Different behavioral profiles of the non-peptide substance P (NK1) antagonists CP-96,345 and RP 67580

    Regul. Pept.

    (1993)
  • G.R Seabrook et al.

    Thapsigargin blocks the mobilisation of intracellular calcium caused by activation of human NK1 (long) receptors expressed in Chinese hamster ovary cells

    Neurosci. Lett.

    (1993)
  • M.B Shaikh et al.

    Evidence that substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat

    Brain Res.

    (1993)
  • R Shigemoto et al.

    Immunocytochemical localization of rat substance P receptor in the striatum

    Neurosci. Lett.

    (1993)
  • Cited by (188)

    • Receptor distribution studies

      2017, Current Opinion in Pharmacology
    • Nicotine and Neurokinin Signaling

      2016, Neuropathology of Drug Addictions and Substance Misuse
    View all citing articles on Scopus
    View full text