Neurokinin-3 receptor distribution in rat and human brain: an immunohistochemical study

Mileusnic, Darinka; Lee, J. M.; Magnuson, Debra J.; Hejna, Matthew J.; Krause, James E.; Lorens, James B.; Lorens, Stanley A.

doi:10.1016/s0306-4522(98)00349-2

Cited by 127 publications

(101 citation statements)

References 64 publications

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“…Immunohistochemical studies have demonstrated NK1 and NK3 receptor expression in the PAG (Barbaresi, 1998;Mileusnic et al, 1999;Yip and Chahl, 2001;Commons and Valentino, 2002), and we have previously shown that the postsynaptic actions of substance P on PAG neurons are mediated in part by NK1, NK2, and NK3 receptor subtypes (Drew et al, 2005). In the present study, although an NK1 receptor-specific antagonist significantly reduced substance P-induced suppression of evoked IPSCs, this effect was completely abolished only when a combination of NK1, NK2, and NK3 antagonists was used.…”

Section: Presynaptic Inhibition Mediated By Local Glutamatergic Transsupporting

confidence: 40%

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Drew¹,

Lau²,

Vaughan³

2009

J. Neurosci.

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Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA B , ,␦-opioid, adenosine A 1 , and 5HT 1A receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.

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Section: Presynaptic Inhibition Mediated By Local Glutamatergic Transsupporting

confidence: 40%

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Drew¹,

Lau²,

Vaughan³

2009

J. Neurosci.

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“…However, NK 3 -mediated functional changes in these nuclei, measured using electrophysiological recordings and subsequent neurochemical output, have been demonstrated (Navilaiko et al, 1997;Marco et al, 1998). PCR (Buell et al, 1992) and, more recently, immunocytochemistry techniques (Mileusnic et al, 1999;Koutcherov et al, 2000) have established that NK 3 receptors are also expressed, albeit in low abundance, in the primate CNS and human distribution studies have shown that the deep-layer cortical distribution appears to be maintained (Tooney et al, 2000). However, no NK 3 receptors have been detected, to date, within the mesencephalic dopaminergic neurons (Dietl and Palacios, 1991;Whitty et al, 1994Whitty et al, , 1997.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia

Dawson

Cato

Scott

et al. 2007

Neuropsychopharmacol

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Neurokinin-3 (NK 3 ) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK 3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK 3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK 3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK 3 receptors (pK i 8.7) and demonstrates selectivity over other neurokinin receptors (pK i NK 2 ¼ 6.6 and NK 1 o4). In native tissuebinding studies, talnetant displayed high affinity for the guinea pig NK 3 receptor (pK i 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA 2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pK B ¼ 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pK B ¼ 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK 3 receptors. Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK 3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.

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“…At this time, no information is available as to the effects of NK 3 receptor antagonists or agonists in depression or other clinical disorders. NK 3 receptor mRNA expression and receptor immunoreactivity have been found in human brain tissue (Buell et al 1992;Mileusnic et al 1999), providing a potential substrate for any therapeutic action of drugs targeting NK 3 receptors. In view of the strong activating effects of NK 3 agonists upon the 5-HT system, both locally and globally, further exploration into the role of 5-HT in clinical aspects of NK 3 receptor function would be warranted.…”

Section: Behavioral and Clinical Implicationsmentioning

confidence: 99%

“…Both, SP and NKB immunoreactive nerve fibers and terminals have been detected in the DRN (Cuello and Kanazawa 1978;Marksteiner et al 1992). In situ hybridization studies show that there are NK 1 receptor mRNA-positive neurons in the periaqueductal gray and DRN (Maeno et al 1993) and NK 3 receptor mRNApositive neurons in various raphe nuclei, including the DRN (Ding et al 1996;Mileusnic et al 1999). However, it has been reported recently that NK 1 receptors in the DRN are located on non-5-HT neurons rather than 5-HT neurons (Froger et al 2001).…”

mentioning

confidence: 97%

Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus

Liu

Ding

Aghajanian

2002

Neuropsychopharmacology

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Neurokinin-3 receptor distribution in rat and human brain: an immunohistochemical study

Cited by 127 publications

References 64 publications

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia

Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus

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