Central antinociceptive effects of lysine-vasopressin and an analogue

Vasopressin (VP) neurons project to extrahypothalamic sites involved in pain perception, including the substantia gelatinosa of the spinal cord as well as the trigeminal and vagus nerves. Previous studies have reported antinociceptive activity following intracerebroventricular (ICV) or subcutaneous (SC) VP injections (16–100 μg) on the tail-flick test while hyperalgesia has been observed in rats either genetically deficient in VP or treated with antisera to VP. The present study investigated whether nanogram (ng) doses of lysine-vasopressin (LVP) and a VP analogue with prolonged activity increased tail-flick latencies and flinch-jump thresholds following ICV or SC injections. LVP (150 and 500 ng, ICV) significantly increased tail-flick latencies while the analogue 1-deamino-(8-Lys-N^?-(Gly-Gly-Gly))-VP (500 ng, ICV) produced more powerful and prolonged analgesia. In contrast, latencies were not increased by SC injections of LVP (150–1500 ng). Further, flinch-jump thresholds were affected minimally by either ICV or SC LVP injections. These data suggest a role for VP in pain modulation and a central site of this action.     

Central injections of arginine vasopressin prolong extinction of active avoidance

Behavioral and physiological effects of arginine vasopressin (AVP) were examined following intracerebroventricular (ICV) injection in the rat. ICV injections prolonged extinction of active avoidance at doses of 1.0 and 10.0 ng/rat and this effect was blocked by peripheral injection of the vasopressor antagonist of vasopressin [dPtyr(Me)AVP] at a dose of 30 micrograms/kg (SC). However, 1.0 ng of AVP ICV failed to alter systemic blood pressure and also failed to produce taste aversions in a one or two bottle test. Results suggest that central AVP has a central action independent of systemic changes in blood pressure, but that the receptor mediating this action is functionally similar to the AVP V1 (vasopressor) receptor.     

Potentiation of vasopressin analgesia in rats treated neonatally with monosodium glutamate

The analgesic response elicited by central administration of arginine vasopressin (AVP) appears to be dependent upon the integrity of the hypothalamic paraventricular nucleus (PVN), since lesions placed in the PVN eliminate AVP analgesia. A projection to the zona externa of the median eminence constitutes one of the VP-containing efferents of the PVN. Neonatal treatment with monosodium glutamate (MSG) destroys perikarya of the arcuate nucleus and median eminence. The present study examined whether AVP analgesia was affected in the MSG-treated rat and whether these alterations were accompanied by specific changes in VP immunoreactivity in the zona externa of the median eminence. Female rats, neonatally treated with either MSG or a saline control, were tested as adults on the tail-flick test following intracerebroventricular injections of 0, 75, 150 and 500 ng doses of AVP. After testing, selected animals were prepared for AVP and oxytocin immunocytochemistry of the median eminence. Significant potentiations in the magnitude of AVP analgesia were observed in MSG-treated rats. AVP and oxytocin immunoreactivity in the zona interna and oxytocin immunoreactivity in the zona externa of the median eminence were similar in MSG-treated and control rats. In contrast, AVP immunoreactivity in the zona externa of the median eminence was markedly reduced in the MSG-treated rat. These data suggest that VP analgesia may normally be inhibited by those medial-basal hypothalamic neurons affected by neonatal MSG treatment.     

Elimination of vasopressin analgesia following lesions placed in the rat hypothalamic paraventricular nucleus

Pain thresholds are increased following central administration of arginine vasopressin (AVP), an effect which appears not to be mediated through opioid analgesic processes. In addition to magnocellular projections to the posterior lobe of the pituitary gland and parvocellular projections to the zona externa of the median eminence, the paraventricular nucleus (PVN) of the hypothalamus contains VP parvocellular neurons which also project to extrahypothalamic structures involved in pain inhibition. The present study examined whether AVP analgesia as measured by the tail-flick test was altered in animals with lesions placed in the PVN at either 7 or 35 days after surgery. VP levels in the pons-medulla and the lumbo-sacral spinal cord were measured by radioimmunoassay, as well as VP-like immunoreactivity in the PVN and spinal cord with immunocytochemistry. Lesions placed in the PVN eliminated AVP analgesia on the tail-flick test at both 7 and 35 days after surgery, and decreased radioimmunoassayable VP by 59% in the lumbo-sacral spinal cord and 36% in the pons-medulla. The extent of the lesions ranged from complete destruction of the PVN to partial sparing of ventro-medial PVN cells with VP-like immunoreactivity. These data indicate that the PVN is a critical structure for the integrity of AVP analgesia.     

Effects of nonapeptide antagonists on oxytocin- and arginine-vasopressin-induced analgesia in mice

Several peptides, including arginine-vasopressin (AVP), neurotensin, and substance P, produce analgesia that is not mediated by opiate systems. Using the hot plate test, we studied the analgesic effects of intracisternal (i.c.) administration of various doses of the nonapeptide oxytocin (OXY) in Swiss-Webster mice. We found that OXY (1-4 micrograms) significantly increased the latency of animals to jump or lick their paws after placement on a hot plate. This effect was not blocked by naloxone pretreatment, which suggests that it is not opiate dependent. Using the hot plate test, we confirmed that AVP (1 and 4 micrograms) also produces analgesia. We then studied the analgesia produced by OXY and by AVP using 3 nonapeptide analogues with antagonist properties: [Pen1, LpMePhe2, Thr4, Orn8]OXY (PLMPTO-OXY) that has anti-oxytocic properties in the uterine contraction assay, d(CH2)5Tyr(Me)AVP(dTM-AVP) which antagonizes the antidiuretic properties of AVP and d(CH2)5D-Ile2,Abu4-AVP (dIA-AVP) which antagonizes the vasopressor effects of AVP. Simultaneous administration of PLMPTO-OXY completely blocked the analgesia produced by OXY whereas the antidiuretic antagonist dIA-AVP partially blocked OXY-induced analgesia and dTM-AVP had no effect. None of the antagonists used blocked AVP-induced analgesia. We concluded that the neural systems mediating the analgesic effects of i.c. OXY differ from those for AVP.     

Only through the brain nuclei, arginine vasopressin regulates antinociception in the rat

The effect of arginine vasopressin (AVP) on rat antinociception was investigated. Intraventricular injection of 50 or 100 ng AVP dose-dependently increased the pain threshold; in contrast, intraventricular injection of 10 μl anti-AVP serum decreased the pain threshold; both intrathecal injection of 200 ng AVP or 10 μl anti-AVP serum and intravenous injection of 5 μg AVP or 200 μl anti-AVP serum did not influence the pain threshold. Pain stimulation reduced AVP concentration in hypothalamic paraventricular nucleus (PVN), and elevated AVP concentration in hypothalamic supraoptical nucleus (SON) and periaqueductal gray (PAG), but no change in AVP concentration was detected in pituitary, spinal cord and serum. The results indicated that AVP regulation of antinociception was limited to the brain nuclei.     

Arginine vasopressin in the caudate nucleus plays an antinociceptive role in the rat

Our previous work has shown that arginine vasopressin (AVP) regulates antinociception through brain nuclei rather than the spinal cord and peripheral organs. The present study investigated the nociceptive effect of AVP in the caudate nucleus (CdN) of the rat. Microinjection of AVP into the CdN increased pain threshold in a dose-dependent manner, while local administration of AVP-receptor antagonist-d(CH(2))(5)Tyr(Et)DAVP decreased pain threshold. Pain stimulation elevated AVP concentration in CdN perfuse liquid. CdN pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the CdN. The data suggest that AVP in the CdN is involved in antinociception.     

中缝大核在刺激视上核镇痛中的作用

运用核团灌流液的放免测定和高压液相色谱法以及核团内注射拮抗剂,观察了化学刺激下丘脑视上核（ＳＯＮ）对中缝大核（ＮＲＭ）灌流液内催产素（ＯＴ）、精氨酸加压素（ＡＶＰ）和５－羟色胺（５－ＨＴ）含量的影响以及ＮＲＭ内注射ＡＶＰ、５－ＨＴ或ＯＴ受体拮抗剂对痛阈（ＰＴ）的影响。结果表明：ＳＯＮ内注射Ｌ－谷氨酸（Ｌ－Ｇｌｕ）１０μｇ后动物痛阈明显升高,ＮＲＭ灌流液中ＯＴ和５－ＨＴ的含量明显高于对照组水平,ＡＶＰ的含量仅有一过性增加。ＮＲＭ内注射ｏＴ或５－ＨＴ拮抗剂可逆转化学刺激ＳＯＮ引起的镇痛作用;而ＡＶＰ的Ｖ＿(１／２)受体拮抗剂也轻度抑制这种镇痛作用,但Ｖ＿１拮抗剂对此作用无影响。以上结果提示：在刺激ＳＯＮ镇痛中,ＯＴ起着重要作用,Ｌ－Ｇｌｕ刺激ＳＯＮ的ＯＴ细胞释放ＯＴ,作用于ＮＲＭ细胞的ＯＴ受体和Ｖ＿２受体而产生镇痛作用,５－ＨＴ在此过程中也发挥重要作用。     

Arginine vasopressin induces periaqueductal gray release of enkephalin and endorphin relating to pain modulation in the rat

Previous study has proven that microinjection of arginine vasopressin (AVP) into periaqueductal gray (PAG) raises the pain threshold, in which the antinociceptive effect of AVP can be reversed by PAG pretreatment with V2 rather than V1 or opiate receptor antagonist. The present work investigated the AVP effect on endogenous opiate peptides, oxytocin (OXT) and classical neurotransmitters in the rat PAG. The results showed that AVP elevated the concentrations of leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek) and beta-endorphin (beta-Ep), but did not change the concentrations of dynorphinA(1-13) (DynA(1-13)), OXT, classical neurotransmitters including achetylcholine (Ach), choline (Ch), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate (Glu), dopamine (DA), norepinephrine (NE) and epinephrine (E), and their metabolic products in PAG perfusion liquid. Pain stimulation increased the concentrations of AVP, L-EK, M-Ek, beta-Ep, 5-HT and 5-HIAA (5-HT metabolic product), but did not influence the concentrations of DynA(1-13), OXT, the other classical neurotransmitters and their metabolic products. PAG pretreatment with naloxone - an opiate receptor antagonist completely attenuated the pain threshold increase induced by PAG administration of AVP, but local pretreatment of OXT or classical neurotransmitter receptor antagonist did not influence the pain threshold increase induced by PAG administration of AVP. The data suggested that AVP in PAG could induce the local release of enkephalin and endorphin rather than dynophin, OXT and classical neurotransmitters to participate in pain modulation.     

Characterization of intrathecal vasopressin-induced antinociception, scratching behavior, and motor suppression.

Intrathecal (IT) administration of vasopressin produces antinociception, scratching behavior, and motor suppression. The present experiments characterized these effects with regards to the following: 1) VP receptor specificity, 2) possible involvement of endogenous opiates, 3) possible involvement of seizure activity, and 4) whether the antinociception is due to direct actions of VP at the spinal cord. These studies showed that IT administration of a V1-specific vasopressin antagonist completely blocked the antinociception, scratching behavior, and motor suppression produced by 25 ng IT vasopressin. Furthermore, IT administration of the vasopressin metabolite, [pGlu4,Cyt6]AVP(4-9), produced none of the effects produced by vasopressin. Systemic administration of the opiate antagonists naloxone (1 mg/kg IP) and naltrexone (10 mg/kg IP) had no significant effect on the antinociception produced by IT vasopressin, whereas naltrexone potentiated the scratching behavior. Neither the IT vasopressin-induced antinociception nor scratching behavior was affected by pretreatment with the anticonvulsant sodium valproate. In addition, IT vasopressin inhibited the tail flick reflex in rats with transected spinal cords, demonstrating direct spinal effects of vasopressin. In conclusion, IT administration of vasopressin produces antinociception, scratching behavior, and motor suppression via activation of VP-specific receptors in the spinal cord.     

The effects of pituitary adenylate cyclase-activating polypeptide on acute and chronic morphine actions in mice

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were investigated in mice. The heat-radiant tail-flick test was used to assess antinociceptive threshold. Intracerebroventricular (i.c.v.) administration of PACAP alone had no effect on pain sensitivity but in a dose of 500 ng, it significantly diminished the analgesic effect of a single dose of morphine (2.25 mg/kg, s.c.). PACAP (500 ng, i.c.v.) significantly increased the chronic tolerance to morphine and enhanced the naloxone (1 mg/kg, s.c.)-precipitated withdrawal jumping. Theophylline (1 mg/kg, i.p.) pretreatment significantly enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on tolerance and withdrawal were unaffected upon theophylline administration. On the grounds of our previous studies with vasoactive intestinal polypeptide (VIP), it appears that different receptors are involved in the effects of PACAP in acute and chronic morphine actions. Our results indicate that PACAP-induced actions likely participate in acute and chronic effects of morphine and suggest a potential role of PACAP in opioid analgesia, tolerance and withdrawal.     

Kentsin: tetrapeptide from hamster embryos produces naloxone-sensitive effects without binding to opioid receptors

The opioid nature of kentsin (Thr-Pro-Arg-Lys) and its ability to alter pain perception and intestinal transit were examined. Kentsin (30,000 nM) did not inhibit electrically stimulated contractions of the guinea pig ileum (GPI) or mouse vas deferens (MVD), nor did it cause a rightward displacement of the inhibitory concentration-response curves of the mu-selective opioid agonist PL017 in the GPI or the delta-selective agonist DPDPE in the MVD. Kentsin (10,000 nM) did not displace [3H] naloxone from rat brain homogenates. These results indicate that kentsin lacks opioid agonist and mu and delta opioid antagonist properties and does not bind to opioid receptors. In vivo, kentsin produced dose-dependent analgesia in both the hotplate and abdominal stretch tests when administered intracerebroventricularly (ICV) and intrathecally but not intravenously. The central analgesic effect of kentsin was partially antagonized by the opioid antagonist naloxone. Kentsin inhibited intestinal transit in a dose-dependent manner after ICV administration only. The intestinal antitransit effect of kentsin was not blocked by pretreatment with naloxone. These results suggest that kentsin acts centrally to produce both opioid and non-opioid effects. Further, the opioid-mediated analgesic effects of kentsin involve mechanisms other than direct interaction with opioid receptors.     

Centrally administered vasopressin antagonizes pentobarbital-induced narcosis and depression of hippocampal cholinergic activity

Intracerebroventricular (ICV) microinjection of arginine vasopressin (AVP) to pentobarbital-anesthetized rats produced shortening of the duration of narcosis. This analeptic effect was blocked by atropine, indicating the central cholinergic nature of the response. AVP also increased hippocampal sodium-dependent high affinity choline uptake activity that had been depressed by the barbiturate. The AVP analeptic effect was blocked by pretreatment with a V-1 (vasopressor), but not a V-2 (antidiuretic), vasopressin receptor antagonist. These results suggest that ICV AVP produces its analeptic effect by interacting with central V-1 receptors to activate a hippocampal cholinergic arousal system. The cholinergic arousal effect may be a factor in the memory enhancing property of AVP.     

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of vasopressin and prostaglandins in the nonpregnant human uterus

The interaction of vasopressin (VP) and prostaglandins (PG) on the nonpregnant human uterus was studied in vitro and in vivo. In organ baths arginine (A)- and lysine (L)-VP in concentrations of 0.6 to 100 ng/ml stimulated small human myometrial strips and uterine artery preparations to a similar degree. When these VPs were given in the presence of indomethacin or naproxen in concentrations of 1 microgram/ml and 5 micrograms/ml, respectively, the myometrial and arterial responses were not significantly influenced. PGF2 alpha in concentrations of 0.01-100 ng/ml stimulated the myometrial preparations but caused a slight relaxation of the arteries, with PGE2 the myometrial effects were insignificant and the relaxation of the arteries greater. When AVP was given together with either of the PGs to the bath the result was generally a summation of the individual effects of both types of substances.--In vivo during intrauterine pressure recordings in nonpregnant women 1-2 days before onset of menstruation LVP in single intravenous injection of 1.2 micrograms markedly stimulated uterine contractions. The response remained practically unaltered after pretreatment with 500 micrograms of naproxen given orally. The responses to LVP were also closely similar before, during and after intravenous infusion of PGF2 alpha at a rate of 5 micrograms/min.--It is concluded that the effect of VP on myometrium and uterine arteries is not to any great extent mediated by local synthesis of PG and that PGs do not cause potentiation or inhibition of the VP effects on the nonpregnant uterus.     

Arginine vasopressin and a vasopressin antagonist peptide: Opposite effects on extinction of active avoidance in rats

Systemic injection of arginine vasopressin (AVP) (1 μ/rat) significantly prolonged extinction of a pole-jump, active avoidance response in rats; lateral ventricular injection of 1000-fold less AVP (1 ng/rat) produced similar results. A new AVP analogue, [1-deaminopenicillamine-2-(O-methyl)-tyrosine]arginine vasopressin (dPTyr-(Me)AVP), is known to antagonize behavioral and vascular effects of exogenous AVP at molar ratios of 5:1. At a dose of 100 μ/rat (subcutaneously) dPTyr-(Me)AVP produces, by itself, a behavioral effect opposite to that of exogenous AVP, namely a facilitation of extinction. Injections of dPTyr-(Me)AVP into the lateral ventricle were ineffective except at a dose of 10 μg/rat. These results confirm previous reports of the effect of vasopressin on delaying extinction of avoidance behavior, but suggest a site of action distant from the lateral ventricle.     

Effect of intranasal arginine vasopressin on human headache

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood–brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.     

下丘脑室旁核加压素能神经元参与电针刺激对实验性...

It has been demonstrated in animal model of somatic pain that hypothalamic paraventricular nucleus (PVN) participates in acupuncture analgesia, probably by mediation of vasopressin release. The role of PVN in acupuncture analgesia for experimental visceral pain in rats was further investigated in the present study. Experimental results demonstrated that electroacupuncture could inhibit the writhing response, produced by intraperitoneal injection of antimonium potassium tartrate and this inhibitory effect could be enhanced by electrical stimulation of PVN, but decreased by electrolytical lesion of PVN, intracerebroventricular injection of vasopressin antiserum (14 microliters) or the vasopressin antagonist, d(CH2)5Tyr(Me)-AVP (500 ng/5 microliters). Intraperitoneal administration of the latter drug (10 micrograms/kg), however, was ineffective. The above experimental results suggest that vasopressinergic neurons in PVN also participate in the inhibition of visceral pain by electroacupuncture.     

Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure

Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.     

Effects of peripherally injected vasopressin and des-glycinamide vasopressin on the extinction of a spatial learning task in rats

An elevated eight-arm radial maze was employed to study the effects of neuropeptide administration on the spatial learning abilities of food-deprived rats. Following 18 days of reinforced training, each animal was briefly exposed to the maze with no food available in any of the eight food-cups. Immediately after this preliminary trial, animals were injected with a single subcutaneous dose of either saline, arginine vasopressin (AVP: 1.0 or 5.0 micrograms/kg), or an AVP analog with only weak endocrinological activity, des-gly-arginine vasopressin (DG-AVP: 1.0, 5.0 or 10.0 micrograms/kg). Additional extinction trials were conducted at 2, 4, 6 and 8 h post-injection. These tests consisted of individually placing an animal on the empty maze and recording the number of arms chosen in a 5-min period. In this situation, animals learn that food is no longer present in the maze and, consequently, extinguish responding. Vasopressin potentiated this radial maze extinction behavior while DG-AVP produced behavioral results directionally opposite to those predicted by a memory facilitation hypothesis. In a subsequent experiment, vasopressin had no effects on unconditioned locomotor activity measured 2 and 4 h post-injection. These results suggest that: vasopressin improved the learning that occurred during extinction of conditioned appetitive behaviors, these vasopressin effects on conditioned behavior were independent of any unconditioned, sedative or non-specific actions of the peptide, and peripheral endocrinological responses may be necessary to demonstrate memory-enhancing effects following peripherally administered AVP.