Substance P and effects of ethanol on the central mechanisms of the escape reaction in rabbits

Substance P (SP) effects on the central mechanisms of escape reaction, elicited by threshold electrical stimulation of the ventromedial hypothalamus were investigated in rabbits pretreated with ethanol (0.5 g/kg). SP (30 micrograms/kg) was demonstrated to normalize in 71.4% of cases the excitability of the ventromedial hypothalamus which was decreased by ethanol and restored in 83.3% of cases the facilitatory effects of the midbrain reticular formation in escape reactions. However, SP was ineffective in the restoration of the inhibitory effects of the dorsal hippocamp on the excitability of the ventromedial hypothalamus that was obvious in intact animals. Partial normalizing effect of SP on escape reaction in rabbits after previous ethanol administration can be accounted for by the fact that both undecapeptide and ethanol are similar in their realization of central effects such as an interaction with the same brain neurotransmitters, interference with neuronal enzyme processes and reactions with opiate receptors.     

Substance P receptors in mammalian central nervous system.

1. Multiple distinct affinity states or sites of substance P (SP) receptors exist in freshly-prepared rat brain membranes. 2. Substance P receptors may couple with islet-activating protein (pertussis toxin) sensitive GTP-binding protein(s). 3. Substance P receptors may be regulated Mg2+ and Na+ in an opposite manner. 4. Some important factor(s), in addition to GTP-binding protein, appear to be involved in SP binding activity. 5. An apparent molecular weight of the SP binding site is approximately 46,000 Da.     

Enhancement of the resistance of the escape reaction to ethanol after substance P]

An ability of substance P (30 micrograms/kg intravenously) to prevent deleterious effects of ethanol (E) (0.5 g/kg intravenously) on central mechanisms of escape reaction elicited by threshold electrical stimulation of the ventromedial hypothalamus was investigated in chronic experiments upon rabbits. Substance P was found to prevent E effects on excitability of the ventromedial hypothalamus (VMH) and on facilitatory influences of the midbrain reticular formation on this emotional centre which were observed in intact animals. Inhibitory effects of the dorsal hippocampus on the VMH could not be evaluated due to its alterations in response to previous substance P administration. The authors suggest that substance P can be considered to be a possible endogenous factor to increase a tolerance of emotional behavioural reactions of an organism to alcohol.     

细胞色素P450酶催化反应动力学研究进展

细胞色素P450是内质网膜上混合功能氧化酶系统的末端氧化酶,在生物体内分布广泛,主要催化机体内源和外源性物质在体内的氧化反应.细胞色素P450种类的多样性、催化反应类型的多样性以及底物的广谱性使其成为自然界最具催化作用的生物催化剂.在临床药物的生物学转化中,它参与大部分药物的生物氧化,因此具有重要的生物学意义.本文主要对细胞色素P450的催化反应机理,尤其是细胞色素P45催化下乙醇氧化的反应机理,及其在药代动力学方面的研究进行了综述.     

Substance P

Substance P is a potent hypotensive peptide first noted in extracts of equine brain and intestinal tissue in 1931 that also stimulates the contraction of various intestinal tissues. Its isolation proved to be particularly difficult and was not accomplished until 1970 following the chance finding of a sialogogic factor in bovine hypothalamic extracts. Utilizing this biological property to monitor purification procedures, the active sialogogic peptide was obtained in pure form and identified as Substance P by multiple chemical and biological criteria. The amino acid sequence of Substance P is HArgProLysProGlnGlnPhePheGlyLeuMetNH₂. Synthetic Substance P has been prepared and a radioimmunoassay has been developed, thus facilitating well-defined research into its physiological roles. Much of the current research is centering on its possible role in sensory neurotransmission.     

Tumor escape mechanisms in prostate cancer

Numerous immunotherapy trials have been carried out in prostate cancer (PC) patients, with induction of antigen-specific T cells in some cases. Despite this capability, limited success is seen in terms of tumor regression or survival. In this review, we discuss the evidence for tumor escape strategies that may contribute to vaccine failure in the setting of PC. These include defects in antigen presentation, production of immunosuppressive substances, induction of T cell death, T cell receptor dysfunction, and the presence of tolerogenic dendritic cells and regulatory T cells inside prostate tumors. It is clear that novel strategies aimed at preventing tumor escape, such as small molecular weight inhibitors of immunosuppressive molecules, adoptive transfer of TCR transgenic T cells, removal of Tregs, combined with anti-androgen therapy and prostate-specific vaccines, need to be examined further in PC patients.This article is a symposium paper from the conference Progress in Vaccination against Cancer 2005 (PIVAC 5), held in Athens, Greece, on 20–21 September 2005.     

Substance P in the central mechanism of the rabbit feeding response evoked by stimulation of the lateral hypothalamus

The effects of substance P on the central mechanisms of food motivation elicited by electrical stimulation of the lateral hypothalamus were studied in chronic experiments on rabbits. Intravenous injection of substance P (30 micrograms/kg) brought about a dramatic reduction in the excitability of the "food center" in the hypothalamus, which returned to normal 45-60 minutes after injection. Higher concentrations of substance P provoked food behavior inversion up to the replacement of food motivation by avoidance behavior. Intravenous injections of substance P disturbed the relationships between the hippocamp, midbrain reticular formation and hypothalamus seen in health. This manifested in complete cessation of the inhibitory effects of the dorsal hippocamp and facilitating influences of the midbrain reticular formation on the excitability of the hypothalamic "food center". It is assumed that disorders of the central mechanisms of food motivation may arise from the effects produced by substance P directly on the central nervous system or on the brain via changes in the hormonal balance and responses of the autonomous nervous system.     

衣原体免疫逃逸机制的研究进展

衣原体是一类专性细胞内寄生的原核细胞型微生物,感染人体后可引起多种慢性疾病。衣原体在宿主细胞中复制和持续性存在是其致病的主要原因。近年的研究表明,衣原体通过改变MHC抗原表达、干扰宿主细胞凋亡信号通路等机制以逃逸宿主的免疫清除。     

Synthesis of Substance P

SUBSTANCE P has been synthesized by the solid-phase procedure of Merrifield^1,2 according to the sequence H-Arg-Pro-LysPro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂ reported in the previous letter.     

Substance P levels in various regions of the rat central nervous system after acute and chronic morphine treatment

Substance P levels were measured in various CNS regions from rats treated acutely and chronically with morphine. There was no observable effect in the group treated with an acute dose of morphine (10 mg/kg) and sacrificed after 2 h. After 35 days chronic treatment with increasing doses of the drug, the rats were divided into three groups and sacrificed 2 h, 24 h and 7 days after the last injection. The substance P level was increased in the corpus striatum 2 h and 24 h and in the medulla oblongata and dorsal part of the spinal cord 2 h after withdrawal. Seven days after the last injection the levels had returned to normal in these areas. No effects were observed in the cerebral cortex, the hypothalamus or the ventral spinal cord at any time of measurement. Earlier studies have demonstrated that morphine inhibits release of substance P. The observed increase in tissue levels after long-term treatment is therefore interpreted as an accumulation of substance P in the neurons.     

Study of lever-holding phenomenon during the escape reaction in rats

A "preparatory" hypothesis according to which the bar-holding develops as a preparatory response placing an animal in an advantageous position for the reaction on the subsequent action of the electric current has been experimentally examined. Comparing the avoidance training under the condition allowing the bar-holding until the next conditioned and unconditioned stimuli, and under conditions excepting such long holding it has been established that in first case the number of bar-holding responses is more and the avoidance responses are less than in the second one. It contradicts the "preparatory" hypothesis. It has been shown that the dynamics of inter-trail and the bar-holding responses results from stimulus generalization and discrimination.     

Substance P and antinociception

Substance P (SP)-induced antinociception is still a topic of controversy. Some investigators have failed to see an antinociceptive effect of SP, particularly following intraperitoneal administration. In the present experiments SP induced significant hot plate antinociception in male mice, following intraperitoneal administration. SP exhibited a bell-shaped dose response curve, and the antinociceptive effect was dependent on the pH of the vehicle. The antinociceptive effect of SP lasted for at least 1 hr and was naloxone-reversible. The antinociceptive effect of SP could be prevented by housing subjects collectively rather than individually during the experiment. In conclusion, the bell-shaped dose response curve, the solution pH and different testing procedures all influence the effects of SP on nociception. Given this complexity, it is not surprising that some experiments fail to demonstrate antinociception following SP administration.     

Substance P innervation of the rat thymus

Immunohistochemistry for substance P (SP) in the rat thymus revealed fine varicose neural profiles in specific regions of the thymus. Thymic SP innervation was abundant within the capsule and interlobular septa. The majority of SP+ nerve fibers within the septa were free of vascular association, although some fibers were associated with the vasculature deep within the septa. SP+ nerve fibers entered the thymic cortex from the septa and distributed among cortical thymocytes and mast cells. Along the corticomedullary junction, SP+ nerve fibers were found in association with the vasculature. The medullary region of the thymus received only a sparse innervation of SP+ fibers. In addition, SP+ nerve fibers coursed adjacent to OX-8+ cells and mast cells in the extrathymic connective tissue surrounding the thymus. The present study provides evidence that SP is present in nerve fibers in the thymus, and may be available to interact with thymocytes, mast calls, and other cells in the thymus, and affect their development and function.     

Amino-acid Sequence of Substance P

IN 1931 von Euler and Gaddum¹, studying the tissue distribution of acetylcholine, found that brain and intestine contained a substance that stimulated contraction of the isolated rabbit jejunum and caused transient hypotension when injected intravenously into anaesthetized rabbits. These effects could not be ascribed to acetylcholine, for they were not prevented by the previous administration of atropine. The initial studies were made on crude acid alcohol extracts of equine brain and intestine, dried in powder form. The active principle in the preparation was later referred to as substance P (P for powder) and this non-committal term subsequently achieved widespread acceptance in the literature, in the absence of any clearly definable biological role for the compound (or compounds) involved.