physalaemin and 7-7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one

A number of neurochemical systems have been implicated in mediating relapse to drug-seeking behavior. Substance P (SP) is a neuropeptide that interacts with some of these systems, suggesting a possible role for SP and its preferred receptor, the neurokinin-1 (NK-1) receptor, in the mediation of relapse. In this study, we examined whether selective activation of NK-1 receptors induces reinstatement of cocaine-seeking behavior, and whether endogenous activity at these receptors is involved in mediating cocaine-induced reinstatement. For each experiment, rats were trained to self-administer cocaine for 8--10 days, and following a period of extinction, tests for reinstatement were given. To examine the effects of NK-1 receptor activation on reinstatement of cocaine-seeking behavior, animals received an intracerebroventricular (ICV) infusion of the selective NK-1 receptor agonist, [Sar(9)Met(O(2))(11)]-SP (0, 1, 3 microg), immediately prior to the test session. To examine the role of endogenous NK-1 receptor activity on cocaine-induced reinstatement, rats were pretreated with ICV infusions of the selective NK-1 receptor antagonists, RP 67580 (0, 0.1, 0.5, 2.5 nmol) or GR 82334 (0, 2, 10, 50 pmol), prior to systemic priming injections of cocaine (10mg/kg or 20mg/kg; i.p.). The results showed that [Sar(9)Met(O(2))(11)]-SP induced reinstatement of cocaine-seeking behavior, but that RP 67580 and GR 82334 had no effect on cocaine-induced reinstatement. These findings suggest that while activation of NK-1 receptors is capable of inducing reinstatement of cocaine-seeking behavior, endogenous activity at these receptors is not involved in mediating the priming effects of cocaine on reinstatement of drug-seeking behavior.

Topics: Animals; Behavior, Addictive; Behavior, Animal; Brain; Cocaine; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Indoles; Infusions, Intravenous; Isoindoles; Male; Physalaemin; Rats; Rats, Wistar; Receptors, Neurokinin-1; Recurrence; Self Administration

Two tachykinin peptides, bufokinin and Xenopus neurokinin A (X-NKA) were recently isolated from Xenopus laevis. In this study we investigated the tachykinin receptors in the Xenopus gastrointestinal tract. In functional studies using stomach circular muscle strips, all peptides had similar potencies (EC50 values 1-7 nM). The rank order of potency to contract the intestine was physalaemin (EC50 1 nM)> or =bufokinin (EC50 3 nM)>substance P (SP)> or =cod SP>NKA>>X-NKA (EC50 1,900 nM). No maximum response could be obtained for [Sar9,Met(O2)11]SP, eledoisin and kassinin. In stomach strips, the mammalian tachykinin receptor antagonists RP 67580 (NK1) and MEN 10376 (NK2) had agonistic effects but did not antagonize bufokinin or X-NKA. In intestinal strips, RP 67580 (1 microM) reduced the maximal response to X-NKA but not bufokinin, while MEN 10376 was ineffective. [125I]BH-bufokinin bound with high affinity to a single class of sites, of KD 213+/-35 (stomach) and 172+/-9.3 pM (intestine). Specific binding of [125I]BH-bufokinin was displaced by bufokinin> or =SP>NKA> or =eledoisin approximately kassinin>X-NKA, indicating binding to a tachykinin NK1-like receptor. Selective tachykinin receptor antagonists were weak or ineffective. Other iodinated tachykinins ([125I]NKA and [125I]BH-eledoisin) displayed biphasic competition profiles, with the majority of sites preferring bufokinin rather than X-NKA. In conclusion, there is evidence for two different tachykinin receptors in Xenopus gastrointestinal tract. Both receptors may exist in stomach, whereas the bufokinin-preferring NK1-like receptor predominates in longitudinal muscle of the small intestine. Antagonists appear to interact differently with amphibian receptors, compared with mammalian receptors.

Topics: Animals; Binding Sites; Cardia; Dose-Response Relationship, Drug; Eledoisin; Female; Indoles; Intercellular Signaling Peptides and Proteins; Intestine, Small; Iodine Radioisotopes; Isoindoles; Kassinin; Male; Muscle Contraction; Muscle, Smooth; Neurokinin A; Peptide Fragments; Physalaemin; Receptors, Tachykinin; Species Specificity; Substance P; Xenopus

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.

Topics: Animals; Antiemetics; Copper Sulfate; Dipeptides; Dose-Response Relationship, Drug; Emetics; Female; Ganglionic Stimulants; Indoles; Infusions, Parenteral; Isoindoles; Male; Motion Sickness; Neurokinin-1 Receptor Antagonists; Nicotine; Physalaemin; Piperidines; Shrews; Stereoisomerism; Vomiting

We investigated the electrocortical (E.Co.G) correlates of visceral (topical capsaicin application or overdistension of the urinary bladder) and somatic (perineal pinching) painful stimulation in urethane-anesthetized rats and their modulation by intrathecal application of selective tachykinins receptors (NK 1 and NK 2) antagonists. Vesical overdistension or topical capsaicin on the bladder serosal surface produced an immediate and lasting E.Co.G. desynchronization resembling a cortical arousal. A second application of capsaicin was ineffective. Bladder contraction induced by topical acetylcholine did not alter E.Co.G. A desynchronized E.Co.G. was also induced by pinching of the perineal area of the rat. Intrathecal administration of lidocaine at lumbosacral level abolished the E.Co.G. desynchronization induced by both visceral and somatic noxious stimulation. On the other hand capsaicin-induced or over-distension (but not pinching-induced) E.Co.G. desynchronization disappeared in animals systemically pretreated with capsaicin or after intrathecal administration of NK 1 tachykinin receptor antagonists such as the peptide GR 82334 or the nonpeptide RP 67580, whereas the inactive enantiomer RP 68651 or the nonpeptide NK 2 antagonists SR 48968 were ineffective. In conclusion, the experimental model described herein, allowing a quantitative analysis of the E.Co.G. correlates of visceral and somatic noxious stimulation in urethane-anesthetized rats, provides evidence for a specific neural pathway carrying bladder-arising visceral (both mechanical and chemical) nociception that uses pelvic capsaicin-sensitive afferents projecting to NK 1 (but not NK 2) bearing spinal neurons and that ultimately leads to activation of cortical areas.

Topics: Acetylcholine; Administration, Topical; Anesthesia; Animals; Benzamides; Capsaicin; Cortical Synchronization; Electric Stimulation; Indoles; Injections, Spinal; Isoindoles; Lidocaine; Male; Perineum; Physalaemin; Piperidines; Rats; Rats, Wistar; Receptors, Tachykinin; Sensitivity and Specificity; Urethane; Urinary Bladder

The effects of substance P (SP) and the selective NK1 receptor agonist [Sar9Met(O2)11] substance P on neonate rat spinal motoneurones were examined using intracellular recordings. Bath-administration of SP (0.1-3 microM) or [Sar9Met(O2)11] substance P (0.01-3 microM) induced a tetrodotoxin (TTX)-insensitive (10 microM) depolarization and a tetraethylammoniumchloride (TEA)-sensitive (3 mM) decrease in membrane conductance. The duration of the slow afterhyperpolarizations (AHPs) following the action potentials were significantly reduced (p = 0.003) by both NK1 receptor agonists. The mean duration of the sAHPs (+/- SEM) in control was 67.8 +/- 6.3 ms whereas in the presence of SP and [Sar9Met(O2)11] substance P their duration was reduced to 41.7 +/- 4.6 ms. Low Ca2+ (0.2 mM)-containing artificial cerebrospinal fluid (ACSF) or addition of BaCl2 or CdCl2 (2 mM) reduced the durations of the slow AHPs by 55%. In the presence of these agents SP and [Sar9Met(O2)11] substance P practically abolished the remaining slow AHPs, suggesting that the agonists also reduce a calcium-independent current. None of the effects induced by the NK1 receptor agonists were antagonized by the NK1 receptor antagonists (+/-)-CP-96,345 (10 microM), RP 67580 (1 microM) or GR 82334 (3-5 microM). In conclusion this study demonstrates that SP and [Sar9Met(O2)11] substance P elicit their effects on NK1 receptors by modulating at least two potassium currents, namely IK and ICa(K).

Topics: Action Potentials; Animals; Animals, Newborn; Biphenyl Compounds; Electric Conductivity; Electric Stimulation; Evoked Potentials; Indoles; Isoindoles; Motor Neurons; Neurokinin-1 Receptor Antagonists; Physalaemin; Rats; Reaction Time; Receptors, Neurokinin-1; Spinal Cord

Tachykinin NK1 receptor antagonists were used to explore the physiological functions of substance P (SP) and neurokinin A (NKA). Pharmacological profiles of three NK1 receptor antagonists, GR71251, GR82334, and RP 67580, were examined in the isolated spinal cord preparation of the neonatal rat. These tachykinin receptor antagonists exhibited considerable specificities and antagonized the actions of both SP and NKA to induce the depolarization of ventral roots. Electrical stimulation of the saphenous nerve with C-fiber strength evoked a depolarization lasting about 30 s of the ipsilateral L3 ventral root. This response, which is referred to as saphenous-nerve-evoked slow ventral root potential (VRP), was depressed by these NK1 receptor antagonists. In contrast, the saphenous-nerve-evoked slow VRP was potentiated by application of a mixture of peptidase inhibitors, including thiorphan, actinonin, and captopril in the presence of naloxone, but not after further addition of GR71251. Likewise, in the isolated coeliac ganglion of the guinea pig, electrical stimulation of the mesenteric nerves evoked in some ganglionic cells slow excitatory postsynaptic potentials (EPSPs), which were depressed by GR71251 and potentiated by peptidase inhibitors. These results further support the notion that SP and NKA serve as neurotransmitters producing slow EPSPs in the neonatal rat spinal cord and guinea pig prevertebral ganglia.

Topics: Animals; Guinea Pigs; In Vitro Techniques; Indoles; Isoindoles; Neurokinin A; Neurokinin-1 Receptor Antagonists; Physalaemin; Rats; Substance P; Synaptic Transmission

The intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before cystometry) induced detrusor hyperreflexia in urethane-anaesthetized rats. Intrathecal administration of the selective tachykinin NK1 receptor antagonist, GR 82,334 ([D-Pro9(spiro-gamma-lactam)Leu10,Trp11]physalaemin-(1-11)) (1 nmol/rat i.t.) had no significant effect on micturition in normal rats but increased the volume threshold In cyclophosphamide-treated rats. Another tachykinin NK1 receptor antagonist, RP 67,580 ((3aR,7aR)-7,7-diphenyl-2-[1-imino-2(2-methoxyphenyl)ethyl]+ ++perhydroisoindol -4-one) (10 nmol/rat i.t.) increased the volume threshold to a similar extent in both vehicle- and cyclophosphamide-treated animals. The tachykinin NK2 receptor antagonist, SR 48,968 (S7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride (10 nmol/rat i.t.) did not modify micturition parameters in normal rats but antagonized bladder hyperreflexia in cyclophosphamide-treated animals; SR 48,968 restored the volume threshold for the micturition reflex to values close to control values. SR 48,965 (R7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride) (10 nmol/rat i.t.), the enantiomer of SR 48,968 devoid of affinity for tachykinin NK2 receptors, was inactive. 2-Amino-5-phosphonovaleric acid (25 and 250 nmol/rat i.t.), a selective antagonist of NMDA receptors, augmented the volume threshold both in controls and in rats with detrusor hyperreflexia; after administration of this antagonist, however, the volume threshold in cyclophosphamide-treated animals was still lower than in controls. Intravenous administration of SR 48,968, RP 67,580, or the combined administration of SR 48,968 and RP 67,580 had no effect on cystometry variables either in rats with detrusor hyperreflexia or in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Animals; Benzamides; Cyclophosphamide; Cystitis; Indoles; Injections, Intravenous; Injections, Spinal; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Physalaemin; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Spinal Cord; Urinary Incontinence; Urination

Topics: 2-Amino-5-phosphonovalerate; 4-Aminopyridine; Afferent Pathways; Animals; Capsaicin; Indoles; Isoindoles; Muscle Contraction; Muscle, Smooth; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Physalaemin; Rats; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Reflex; Spinal Cord; Substance P; Urinary Bladder; Urination