Analgesic activity of substance P following intracerebral administration in rats

Substance P was found to be a potent, long-lasting analgesic in the tail flick test in rats following intracerebral administration, via chronically indwelling cannulae, into the midbrain periaqueductal gray. Substance P was approximately five times as potent as morphine sulfate on a weight basis; however, it was 25 times more potent than morphine on a molar basis. The analgesic activity produced by Substance P was significantly antagonized by pretreatment with naloxone, a narcotic antagonist. The analgesic activity of Substance P exhibited a rapid onset (1 min.), peaked by 3 minutes post infusion and its duration of activity was between 30 and 60 minutes. Thus, Substance P may be yet another endogenous analgesic peptide.     

Analgesic activity of substance P in rats: apparent mediation by met-enkephalin release

The intracerebroventricular administration of Substance P (SP) produced a marked and short-lasting increase in the threshold for vocalization and vocalization afterdischarge in the rat after electrical stimulation of the tail. This effect was blocked by naloxone and potentiated by bacitracin, a peptidase inhibitor. The analgesic effect of SP was also blocked by the concomitant intraventricular injection of the specific antibody against the opioid peptide metenkephalin but not by the antibody against beta-endorphin. Anti-met-enkephalin did not block other pharmacological actions of SP. The results suggest that SP produces an analgesic effect in rats by releasing met-enkephalin at supra-spinal levels involved in pain control.     

Growth hormone and prolactin release by substance P in rats

Intravenous injection of synthetic Substance P resulted in a significant and dose-related increase in plasma growth hormone (GH) and prolactin (PRL) in urethane-anesthetized rats. Increases in plasma GH induced by Substance P were significantly suppressed by the simultaneous administration of either ?-dopa or nicotine, whereas plasma PRL responses to Substance P were blunted by ?-dopa but not by nicotine. Substance P also raised plasma GH and PRL in rats with extensive hypothalamic destruction. L-dopa significantly suppressed plasma PRL responses to Substance P in rats with hypothalamic destruction. However, plasma GH responses to Substance P were not significantly affected by ?-dopa nor by nicotine in animals with hypothalamic ablation. These results suggest that Substance P stimulates rat GH and PRL secretion possibly acting on the anterior pituitary and that ?-dopa and nicotine affect GH and PRL release induced by Substance P in different ways.     

Analgesic and cardiovascular effects of centrally administered substance P

Substance P (SP) injected intracerebroventricularly (ICV) into rabbits caused dose-related thermal analgesia with the maximum effect after 2 micrograms. The analgesia was measured by timing the withdrawal of the rabbit's ear from an infrared beam. Equimolar amounts of the related peptides physalaemin and eledoisin-related peptide also caused analgesia, but the SP N-terminal fragment (1-9) was inactive. This suggests that the analgesic message of SP resides within the C-terminal fragment. The analgesia caused by each peptide developed more rapidly but did not last as long as that after central injection of beta-endorphin. In separate experiments, 2 micrograms SP injected ICV increased blood pressure and decreased heart rate. The analgesic, bradycardic and pressor responses to central administration of SP were opposite to effects of peripherally administered SP, described previously. These results indicate that the effect induced by SP depends upon its specific neuroanatomical site of action.     

Enhancement of phagocytosis - a newly found activity of substance P residing in its N-terminal tetrapeptide sequence

The undecapeptide Substance P stimulates phagocytosis by mouse macrophages and human polymorphonuclear leukocytes. The activity of Substance P resides in its N-terminal tetrapeptide protion. Substance P and its N-terminal tetrapeptide are as active as tuftsin in their phagocytosis-stimulating activity and compete with tuftsin for its binding sites. The phagocytosis-enhancing activity of Substance P may play a role in inflammatory processes of neural origin where the involvement of the peptide has been implicated.     

Activity of substance P analogs substituted at the Gly9 and Gln6 positions

We have prepared peptide derivatives of Substance P in which Gly⁹ or Gln⁶ in the C-terminal part of the molecule have been substituted and we have examined the activity of these peptides using the guinea pig ileum bioassay. Gly⁹ can be substituted without a significant effect on the activity by Ala or Sar but not with DAla or βAla. Derivatives of the C-terminal pentapeptide were prepared and were almost as potent as the undecapeptide Substance P. The results presented are of particular relevance for the future design of radioactive receptor ligands of high affinity, of Substance P antagonists and of affinity labels.     

Distinct classes of substance P receptors revealed by a comparison of the activities of substance P and some of its segments

The contracting potency of Substance P and of its C-terminal fragments was studied using four isolated preparations of smooth muscle. The Substance P receptors in the four muscles studied can be differentiated on the basis of their interactions with Substance P and its C-terminal fragments. On the guinea pig ileum, the potency of Substance P is equal to that of the C-terminal octa- and heptapeptide segments and in the rat ileum the potency of Substance P is equal to that of the C-terminal octapeptide and even higher than that of the heptapeptide. In contrast, on the cow pupillary sphincter and guinea pig urinary bladder, Substance P is markedly less potent that the C-terminal octa-, hepta- and hexapeptides. These results suggest the existence of different classes of Substance P receptors and indicate that the N-terminal sequence may be important in regulating Substance P activity.     

Administration of the anabolic androgenic steroid nandrolone decanoate affects substance P endopeptidase-like activity in the rat brain

The effect of the anabolic androgenic steroid, nandrolone decanoate, on substance P endopeptidase-like activity was examined in adult male Sprague-Dawley rats. Nandrolone decanoate (15 mg/kg day) or oil vehicle (sterile arachidis oleum) were administered by intramuscular injections during 14 days. Substance P endopeptidase, a predominantly cytosolic enzyme, generates the bioactive N-terminal fragment substance P(1-7) from the enzyme substrate substance P. Nandrolone decanoate significantly reduced the substance P endopeptidase-like activity compared to control animals in hypothalamus (43% reduction), caudate putamen (44%), substantia nigra (32%) and the ventral tegmental area (27%). It was previously reported that both hypothalamus and caudate putamen contained significantly higher levels of substance P after nandrolone administration. The higher concentration of substance P in these regions could to an extent be attributed to the reduction in substance P endopeptidase-like activity. This result elucidates the important role of peptidase activity in the regulation of the substance P transmitter system. The present study provides additional support for the hypothesis that alterations in the substance P system in certain brain areas may contribute to some of the personality changes reported in connection with AAS abuse.     

Synthesis and biological activity of substance P C-terminal hexapeptide analogues: structure-activity studies

The synthesis of six hexapeptide analogues of C-terminal Substance P fragment containing alpha, beta-dehydrophenylalanine (delta Phe) in the position 7 or 8 is described. The effect of the structural changes on the hypotensive activity and antigenic properties of analogues was compared. It was found that substitution of delta Phe in various analogues of C-terminal hexapeptide of Substance P resulted in different effects on the hypotensive activity. The analogues [Glp6, delta Phe7]SP6-11 and [Glp6, delta Phe8]SP6-11 retained 70% and 45% of hypotensive activity of the C-terminal hexapeptide of Substance P, respectively but they showed a completely destroyed antigenic determinant. The analogues containing additionally Sar or His in the position 9 showed a complete lack of both: hypotensive activity and expression of the antigenic determinant of Substance P.     

The effects of surgical procedures, halothane anaesthesia and nalbuphine on locomotor activity and food and water consumption in rats

A study was undertaken to investigate the effects of surgical procedures on food and water intake and spontaneous locomotor activity in laboratory rats. The influence of anaesthesia with halothane and administration of the opioid analgesic nalbuphine was investigated in normal rats and in animals which underwent either unilateral nephrectomy or jugular vein cannulation. Both nephrectomy and jugular cannulation were associated with a significant reduction in food and water consumption and a depression in locomotor activity levels. The reduction in activity following nephrectomy was reversed by administration of 6 doses of nalbuphine at 4 hourly intervals. Administration of nalbuphine at the same dose rate following halothane anaesthesia in normal rats resulted in a stimulation of activity. The prevention of the depressant effects of surgery by this opioid appears to be due to its stimulatory effect rather than a specific analgesic action. The degree of depression of food and water consumption after nephrectomy was significantly reduced following 6 doses of nalbuphine. This beneficial effect of repeated administration of an opioid may be related to the compound's analgesic action.     

P物质的免疫调节作用

P物质在外周主要分布于了发出细传入的神经元内。在外周神经末梢释放的P物质参与免疫调节和炎症过程。P物质可以影响淋巴细胞的增殖、免疫球蛋白和细胞因子的合成,并能够调节辅佐细胞的活性和细胞因子的合成以及其他一些免疫细胞的活性。P物质通过以上作用参与调节细胞和体液免疫应答。在外周组织中,P物质能的神经纤维和一些免疫细胞联系密切,许多免疫细胞膜上存在有P物质的特异性受体。这些形态学资料为P物质参与免疫调节提供了证据。一些免疫细胞也能够产生P物质,并以自分泌或／和旁分泌的方式调节免疫细胞的功能。以上资料表明P物质不仅是一种神经肽,也是一种免疫调节因子,是神经系统和免疫系统共同的信使物质。     

Effects of substance P on intestinal circulation and oxygen consumption

The effects of intra-arterial administration of substance P upon intestinal blood flow, oxygen consumption, intestinal motor activity, and distribution of blood flow to the compartments of the gut wall were measured in anesthetized dogs. Blood flow to the segment of distal ileum was measured with an electromagnetic blood flow meter and A-VO2 was measured spectrophotometrically. Oxygen uptake was calculated as the product of A-VO2 and total blood flow. The clearance of 86Rb was measured to estimate the density of the perfused intestinal capillaries. Changes in blood flow distribution were estimated from the distribution of radiolabeled microspheres. Motor activity was monitored from changes in intraluminal pressure. Substance P induced a dose-related increase in intestinal blood flow, oxygen consumption, and intestinal motor activity. A significant increase in 86Rb clearance and increase in blood flow to the muscles was also observed. The results of these studies indicate that substance P relaxes intestinal arterioles and precapillary sphincters thereby inducing intestinal hyperemia and increased oxygen consumption. These changes, at least in part, might be due to the increased intestinal motility with enhanced metabolic demands of the muscularis for oxygen.     

The anti-inflammatory and analgesic effects of a crude extract of Petiveria alliacea L. (Phytolaccaceae).

Petiveria alliacea L (Phytolaccaceae) is a perennial bush plant that grows widely in Brazil. The roots and leaves of P. alliacea have been used in folk medicine for their antispasmodic, sedative, diuretic and antihelminthic actions. We recently described the anti-inflammatory properties of P. alliacea administered topically and orally in different animal models. In the present study, we investigated the anti-inflammatory activity of a crude lyophilized extract of P. alliacea roots administered to rats with pleurisy. The oral administration of P. alliacea root extract did not significantly reduce the total number of leukocytes at the doses tested. By contrast, the highest dose of extract tested (43.9 mg/kg body wt.) significantly reduced the number of migrating neutrophils, mononuclear cells and eosinophils; the dose of 31.4 mg/kg body wt. also reduced mononuclear cell migration. The P. alliacea root extract also showed a significant analgesic effect in the experimental model used. The results of this study provide a basis for the use of P. alliacea extracts in popular folk medicine, but further studies are necessary to elucidate the mechanism of its anti-inflammatory and analgesic actions.     

Effects of substance P on acetylcholinesterase activity

The effects of substance P on acetylcholinesterase activity have been examined. The neuropeptide produced a significant increase in the activity of the enzyme in rat cerebral cortex. Pretreatment of rats with either actinomycin-D or cycloheximide did not fully abolish the substance P-mediated stimulation of cerebral acetylcholinesterase. Substance P increased the enzyme activity in rat brain slices; moreover, substance P increased the activity of electric eel acetylcholinesterase in in vitro experiments. These observations indicate that substance P produces an induction of acetylcholinesterase in cerebral cortex of rats and in addition indicate that a direct action on the enzyme takes place.     

Isolation and identification of a peptide from rat brain which inhibits [3H]TCP binding.

1. A stereospecific radioreceptor binding assay for the phencyclidine analogue [3H]TCP was utilized to screen for inhibitors of binding in extracts of rat brain. 2. Extracts were prepared from rat cortex and hippocampus by methods employing aqueous acid or acidified methanol. Samples were fractionated by reversed phase-HPLC (RP-HPLC) and tested for activity in the radioreceptor assay. Three zones of activity were detected. The most active fraction was further purified by high performance-size exclusion chromatography. 3. Size exclusion chromatography revealed two zones of activity, corresponding to mol. wts of 4000-8000 Da and 1000-2000 Da. Final purification of the lower molecular weight material was achieved by RP-HPLC. 4. Two well-separated peaks were shown to be homogeneous. Their amino acid sequences were determined by automated Edman degradation and data base searching identified these two peaks as the undecapeptide Substance P and its oxidized counterpart (Substance P sulfoxide). 5. Comparative HPLC of synthetic Substance P, or its sulfoxide, as well as spectral analysis confirmed the identity of the isolated peptides. 6. Synthetic Substance P inhibits specific [3H]TCP binding in the radioreceptor assay.     

Substance P binds to the formylpeptide chemotaxis receptor on the rabbit neutrophil

Substance P, a potent vasodilatory and smooth muscle contracting agent, binds specificially to the formyl peptide receptor on the rabbit neutrophil. Substance P stimulates chemotaxis and induces lysosomal enzyme secretion in concentrations which similarily inhibit f Met-Leu-(³H)Phe receptor binding. Competitive antagonists of the formyl peptide receptor also inhibit the activity of Substance P. The finding of a naturally occurring eukaryotic peptide interacting with the neutrophil formyl peptide receptor is of importance.     

Antinociceptive action of intrathecal neurotensin in mice

Neurotensin has been demonstrated to be analgesic in rodents. This study used intrathecal injection of neurotensin in unanesthetized mice to evaluate the effect of the peptide at the spinal level on unconditioned behavior. Intrathecal administration of neurotensin produced dose-related inhibition of locomotor activity and of the response elicited by subcutaneous hypertonic saline. The effects of the peptide in the tail flick assay were variable and it produced no inhibition of the behavioral response to intrathecal substance P. The results indicate that neurotensin antinociception at the spinal level does not result from locomotor impairment, may be somewhat selective for chemically induced pain, and may be mediated by a presynaptic action on primary afferent fibers.     

Cation-dependent substance P activation of the enzyme guanylate cyclase

Substance P enhanced guanylate cyclase (E.C.4.6.1.2) two- to fourfold in pancreas, small intestine, cerebellum, liver, kidney, and lung. Dose response relationship revealed that substance P caused a maximal augmentation of guanylate cyclase activity at concentration of 1 micromolar. Increasing substance P's concentration to the millimolar range caused no further increase in activity. There was an absolute cation requirement for substance P's enhancement of guanylate cyclase activity. Substance P could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of substance P.     

Antinociceptive and gastroprotective effects of inhaled and orally administered Lavandula hybrida Reverchon "Grosso" essential oil

In this study the antinociceptive and the gastroprotective effects of orally administered or inhaled Lavandula hybrida Reverchon "Grosso" essential oil, and its principal constituents linalool and linalyl acetate were evaluated in rodents. Either when orally administered (100 mg/kg) or inhaled for 60 min lavender essential oil significantly reduced the acetic acid-writhing response in a naloxone-sensitive manner. In the hot plate test, analgesic activity observed after oil inhalation was inhibited by naloxone, atropine, mecamylamine pretreatment suggesting the involvement of opioidergic as well as cholinergic pathways. Regardless of the administration route and the experimental model used both linalool and linalyl acetate did not produce significant analgesic response. Oral or inhalatory treatment with analgesic doses of essential oil did not affect mice spontaneous locomotor activity. Concerning the gastric effects, lavender oil, linalool and linalyl acetate oral administration protected against acute ethanol-induced gastric ulcers but did not prevent indomethacin-induced lesions indicating no interference with arachidonic acid metabolic cascade. In conclusion, besides this gastroprotection, lavender oil reveals an interesting analgesic activity mainly relevant after inhalation, at doses devoid of sedative side effect, suggesting the interest for potential application of this oil in aromatherapy.     

Antagonism of morphine tolerance and dependence by metoclopramide

Metoclopramide produced significant analgesic activity when tested by acetic acid induced writhing assay. Repeated injections of metoclopramide did not result in the development of tolerance to its analgesic activity. Pretreatment with metoclopramide antagonised acute morphine tolerance and suppressed the withdrawal signs (both in acute dependence type and abrupt withdrawal type). It is suggested that metoclopramide may be a useful tool in the management of morphine dependence.