Biochemical characterization and autoradiographic localization of central substance P receptors using [125I]physalaemin

Wolf, Steven S.; Moody, Terry W.; Quirion, Rémi; O’Donohue, Thomas L.

doi:10.1016/0006-8993(85)90598-0

Cited by 56 publications

(24 citation statements)

References 27 publications

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“…Apparent dissociation constants (KD) ranging from 3 x 10-10 to 7 x 10-9 M were obtained for radiolabelled substance P or physalaemin bound to brain slices (Rothman et al 1984b;Mantyh et al 1984a;Schults et al 1984;Wolf et al 1985;Mohini, Bahouth, Brundish & Musacchio, 1985), whereas radiolabelled bombesin binding had an apparent KD of 4-6 x 10-9 M (Zarbin et al 1985). The relatively high apparent KD values for the electrophysiological effects may be due to several factors.…”

Section: Effects Of Bombesitnmentioning

confidence: 99%

“…This brain area, and in particular its ventral subdivision, contains scattered substance P immunoreactive fibres (Roberts, Woodhams, Polak & Crow, 1984). Binding sites for radiolabelled substance P or physalaemin have been detected in the hippocampus (Rothman, Herkenham, Pert, Liang & Cascieri, 1984b;Mantyh, Hunt & Maggio, 1984 a;Shults, Quirion, Chronwall, Chase & O'Donohue, 1984;Wolf, Moody, Quirion & O 'Donohue, 1985). Moreover, the distribution of substance P binding sites present in this as well as in other brain regions has been shown to correlate with the amount of substance P-induced hydrolysis of inositol phospholipids in the same areas (Mantyh, Pinnock, Downes, Goedert & Hunt, 1984c).…”

Section: Introductionmentioning

confidence: 97%

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Tachykinins and bombesin excite non‐pyramidal neurones in rat hippocampus.

Dreifuss¹,

Raggenbass²

1986

The Journal of Physiology

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SUMMARY1. The effects of substance P, eledoisin and physalaemin -which are structurally similar and all belong to the tachykinin family -and of bombesin, a gastrin-releasing peptide, on non-pyramidal neurones were studied using unitary extracellular recordings from rat hippocampal slices. The peptides were added to the perifusion solution, or locally applied by pressure ejection from a micropipette, at concentrations ranging from 10-8 to 10-6 M.2. 104 out of 115 non-pyramidal neurones responded to tachykinins, and 26 out of 27 responded to bombesin, by a reversible, concentration-dependent increase in firing.3. The responsive neurones retained their sensitivity to the tachykinins and to bombesin under the condition of synaptic blockade. 4. A synthetic peptide known to antagonize the effects of oxytocin on hippocampal non-pyramidal neurones did not affect the excitations induced by the tachykinins or bombesin. The action of the tachykinins was not blocked by the muscarinic antagonist, atropine.5. These results indicate that hippocampal non-pyramidal neurones -which were previously shown to possess oxytocin receptors and #u-type opiate receptors -bear receptors for peptides of the tachykinin and of the gastrin-releasing families.6. The hippocampal effects of tachykinins and of bombesin, however, were not blocked by synthetic structural analogues of substance P, known to antagonize the action of these peptides on some non-nervous tissues. The possibility must be considered that brain receptors for tachykinins and for gastrin-releasing peptides may be distinct from the peripheral receptors for these peptides.

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Section: Effects Of Bombesitnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Tachykinins and bombesin excite non‐pyramidal neurones in rat hippocampus.

Dreifuss¹,

Raggenbass²

1986

The Journal of Physiology

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“…Potency at substance P receptors was measured by inhibition of specific binding of [ 125 I]physalaemin 15 to the receptors in rat telencephalon slices. The results show that the ability of one molecule to bind to either receptor is achieved when both components are structurally complete, e.g., 1 and 3.…”

Section: Resultsmentioning

confidence: 99%

“…19 It is unknown whether this phenomenon occurs with these binary ligands for two different receptors, but it remains a possibility in light of the high affinity of conjugate 1. It is to be noted that SP receptors 15 and one subclass of A 2 -adenosine receptors both occur in high density in the striatum relative to other brain regions.…”

Section: Discussionmentioning

confidence: 99%

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Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors

Jacobson¹,

Lipkowski²,

Moody³

et al. 1987

J. Med. Chem.

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A "functionalized congener" approach to adenosine receptor antagonists has provided a means to synthesize highly potent peptide conjugates of 1,3-dialkylxanthines. The antagonist XAC, such a functionalized xanthine amine congener, has been attached to a segment derived from the neurotransmitter peptide substance P (SP) to form a binary drug that binds to both receptors with K i values of 35 nM (central A 1 -adenosine) and 300 nM (striatal SP). Coupling of the functionalized adenosine agonist N 6 -[p-(carboxymethyl)phenyl]adenosine to an SP C-terminal peptide also resulted in a binary drug that binds to both receptors. The demonstration that the biochemical properties of two unrelated drugs, both of which act through binding at extracellular receptors, may be combined in the same molecule suggests a novel strategy for drug design. In principle, a combined effect of the two different substances that produce the same final effect (e.g., hypotension by adenosine agonists and by SP analogues) might occur in vivo. Adenosine analogues have analgesic properties, and the binary drug derived from substance P and adenosine agonists or antagonists might provide useful tools for probing interrelationships of SP pathways and sites for the antinociceptive action of adenosine.A "functionalized congener" approach to adenosine receptor antagonists 1,2 has resulted in highly potent 1,3-dialkylxanthines having amino and carboxylic acid functionalized chains. These functional groups have been coupled covalently to amino acids and dipeptides. The resulting amino acid and oligopeptide conjugates have full, and in some cases enhanced, biological activity. In our previous work 2 we used nonhormonal peptide sequences to alter the physicochemical properties of the drugs. We now report the attachment of a xanthine to a segment derived from a putative neurotransmitter peptide, substance P (SP) (reviews, ref 3,4), to form a binary drug 1 (Figure 1). This drug binds both to adenosine receptors and to substance P receptors with affinity comparable to that of each component at the appropriate receptor. In addition, coupling of the adenosine agonist N 6 -[p-(carboxymethyl)phenyl]adenosine, 5 2a, to substance P segment 7-11 produced the binary drug 3, which also binds to both receptors. We have demonstrated a potentially general strategy via "functionalized congeners" for the synthesis of binary drugs that combine pharmacological properties of both elements. The choice of combination of adenosine receptor ligands and substance P in target molecules stems from the peripheral hypotensive effect elicited by agonists for both receptor. 6,7 Moreover, since both receptors mediate central nociceptive effect, 8,9 the binary conjugates may prove to be useful tools in probing neuronal pathways involved in perception of pain. ResultsThe xanthine amine congener (XAC) has several features in its structure that lead to enhanced receptor affinities. Thus, we have found from a study of many xanthine derivatives that an amino group in the appended chain...

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Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: A light and electron microscopic study

Barbaresi

1998

J. Comp. Neurol.

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The distribution of substance P receptor (SPR) protein in the rat periaqueductal gray matter (PAG) was investigated with a polyclonal antibody in the four subdivisions obtained by cytochrome-oxidase histochemistry (Co-hi). At light microscopic analysis, immunoreactivity appeared particularly dense in the dorsal subdivision of the PAG, was less intense in the other subdivisions, and formed several longitudinally organized columns. SPR-like immunoreactivity (SP(R-i)) was localized mostly to cell bodies and dendrites of small and medium-sized neurons, which constituted about 6% of the total neuronal population of the PAG. At the electron microscopic level, SP(R-i) could be observed on postsynaptic as well as on nonsynaptic regions of both cell bodies and dendrites. A small proportion of axons (4.2%) and axon terminals (5.3%) showed SP(R-i), the majority of labeled axon terminals, amounting to about 70% of synapsing elements, formed asymmetric synapses with dendrites. Rare astroglial processes displaying SP(R-i) were also observed scattered throughout the neuropil of all PAG subdivisions. Our observations suggest that 1) also in the PAG, SP may act in a diffuse, nonsynaptic manner, probably on targets that are distant from its sites of release; and 2) SP may modulate excitatory neurotransmission acting presynaptically on those labeled axons that form asymmetric synapses.

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Biochemical characterization and autoradiographic localization of central substance P receptors using [125I]physalaemin

Cited by 56 publications

References 27 publications

Tachykinins and bombesin excite non‐pyramidal neurones in rat hippocampus.

Tachykinins and bombesin excite non‐pyramidal neurones in rat hippocampus.

Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors

Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: A light and electron microscopic study

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