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.     

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.     

Through V2, not V1 receptor relating to endogenous opiate peptides, arginine vasopressin in periaqueductal gray regulates antinociception in the rat

Our previous study has proven that central arginine vasopressin (AVP) plays an important role in antinociception, and pain stimulation raises AVP concentration in the periaqueductal gray (PAG). The nociceptive effect of AVP in PAG was investigated in the rat. The results showed that microinjection of AVP into PAG increased pain threshold, whereas microinjection of V2 receptor antagonist-d(CH2)5[d-Ile2, Ile4, Ala9-NH2]AVP into PAG decreased pain threshold in a dose-dependent manner, but local administration of V1 receptor antagonist-d(CH2)5Tyr(Me)AVP did not change pain threshold; Pain stimulation elevated AVP, Leucine-enkephalin (L-Ek), Methionine-enkephalin (M-Ek) and beta-endorphin (beta-Ep), not dynorphinA(1-13) (DynA(1-13)) concentrations in PAG perfuse liquid; PAG pre-treatment with naloxone, an opiate receptor antagonist or V2 receptor antagonist completely reversed AVP-induced increase in pain threshold, however, PAG pre-treatment with V1 receptor antagonist did not influence this effect of AVP administration. The data suggest that AVP in the PAG, through V2 rather than V1 receptor, regulates antinociception, which progress relates to enkephalin and endorphin.     

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the nucleus raphe magnus to participate in pain modulation

Hypothalamic paraventricular nucleus (PVN) is one of the main sources of arginine vasopressin (AVP) synthesis and secretion. AVP is the most important bioactive substance in PVN regulating pain process. Our pervious study has pointed that pain stimulation induced AVP increase in the nucleus raphe magnus (NRM), which plays a role in pain modulation. The present study was designed to investigate the source of AVP in the rat NRM during pain process using the methods of nucleus push–pull perfusion and radioimmunoassay. The results showed that pain stimulation increased the AVP concentration in the NRM perfusion liquid, PVN cauterization inhibited the role that pain stimulation induced the increase of AVP concentration in the NRM perfusion liquid, and PVN microinjection of l-glutamate sodium, which excited the PVN neurons, could increase the AVP concentration in the NRM perfusion liquid. The data suggested that AVP in the PVN might be transferred to the NRM to participate in pain modulation.     

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。     

Antinociceptive role of oxytocin in the nucleus raphe magnus of rats, an involvement of mu-opioid receptor

Recent studies showed that oxytocin plays an important role in nociceptive modulation in the central nervous system. The present study was undertaken to investigate the role of oxytocin in antinociception in the nucleus raphe magnus (NRM) of rats and the possible interaction between oxytocin and the opioid systems. Intra-NRM injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulation in rats. The antinociceptive effect of oxytocin was significantly attenuated by subsequent intra-NRM injection of the oxytocin antagonist 1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin. Intra-NRM injection of naloxone dose-dependently antagonized the increased HWLs induced by preceding intra-NRM injection of oxytocin, indicating an involvement of opioid receptors in oxytocin-induced antinociception in the NRM of rats. Furthermore, the antinociceptive effect of oxytocin was dose-dependently attenuated by subsequent intra-NRM injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA), but not by the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) or the delta-opioid antagonist naltrindole. The results demonstrated that oxytocin plays an antinociceptive role in the NRM of rats through activating the oxytocin receptor. Moreover, mu-opioid receptors, not kappa and delta receptors, are involved in the oxytocin-induced antinociception in the NRM of rats.     

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.     

Central oxytocin enhances antinociception in the rat

The study aimed to investigate the effect of oxytocin on antinociception in the rat. The pain threshold was elevated by oxytocin following intraventricular (icv) or intrathecal injection (ith), and reduced by anti-oxytocin serum (icv or ith). But the pain threshold was not altered by intravenous injection (iv) of oxytocin or anti-oxytocin serum. Pain stimulation induced oxytocin concentration decrease in the hypothalamic supraoptic nucleus, and increase in the locus coeruleus, raphe magnus nucleus, caudate nucleus and spinal cord, but no change in the hypothalamic paraventricular nucleus and plasma. The results indicated that central, not peripheral oxytocin could enhance antinociception.     

大鼠侧脑室注射精氨酸加压素对针刺镇痛的影响

以钾离子透入法引起大鼠甩尾反应为指标,测定动物的痛阈。由侧脑室注射精氮酸加压素(AVP)后,大鼠痛阈升高33.6％～68.5％,针刺镇痛效应明显加强,痛阈提高202.4％～302.7％。脑室注射抗精氨酸加压素血清,动物痛阈虽无明显变化,但针刺镇痛效应明显削弱,痛阈仅增加41.6％～71.0％。注射抗β-内啡肽血清和抗强啡肽A血清并不阻断AVP增强针刺镇痛效应。本工作的结果提示,脑内AVP参与针刺镇痛,这种作用与脑内内源性β-内啡肽和强啡肽的关系不甚密切。     

生长抑素通过中缝大核发挥镇痛和增强电针镇痛的作用

本工作以钾离子透入引起大鼠甩尾为痛指标,观察了中缝大核微量注射生长抑素、生长抑素的耗竭剂半胱胺和抗生长抑素血清对大鼠痛阈和电针镇痛效应的影响。中缝大核微量注射生长抑素可提高大鼠的痛阈,并使电针镇痛的效应加强。用半胱胺耗竭或用抗生长抑素血清中和中缝大核中的生长抑素,均可使大鼠的痛阈降低,并减弱电针镇痛的效应。这表明生长抑素可能通过中缝大核发挥镇痛和增强电针镇痛的作用。     

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus

Our pervious study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of l-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of l-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.     

Guanine nucleotide regulation of [3H]vasopressin binding to liver plasma membranes and solubilized receptors. Evidence for the involvement of a guanine nucleotide regulatory protein.

A guanine nucleotide regulatory protein may be involved in vasopressin-receptor-mediated polyphosphoinositide breakdown in rat liver. Therefore we examined the effects of the non-hydrolysable guanine nucleotide guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) on [3H]vasopressin ([3H]AVP) binding to hepatic plasma membranes and detergent extracts. [3H]AVP bound to a single set of high-affinity binding sites in membranes. Addition of p[NH]ppG decreased the affinity of receptor binding without altering the maximal binding capacity. The rate of dissociation of [3H]AVP from membrane-bound receptors was also enhanced by p[NH]ppG. Solubilization of [3H]AVP-prelabelled membranes with dodecyl beta-D-maltoside resulted in a [3H]AVP-receptor complex that was unstable in solution. Incubation of these extracts for 5 min at 30 degrees C resulted in a 40% loss of bound [3H]AVP, whereas in the presence of p[NH]ppG there was a 54% loss. However, when membranes were prelabelled with [3H]AVP and p[NH]ppG and then solubilized, the resulting hormone-receptor complex was still temperature-labile but insensitive to the further addition of p[NH]ppG. The molecular size of soluble vasopressin receptors was estimated by gel filtration. The [3H]AVP-receptor complex was eluted as a single peak with an apparent molecular size of 258 kDa. However, no peak was detected when solubilized extract was made from membranes prelabelled with [3H]AVP and p[NH]ppG, suggesting that this receptor complex had dissociated during chromatography. It is possible therefore that the high-Mr complex contains the hormone, its receptor and a guanine nucleotide binding protein.     

Properties of vasopressin-activated human platelet high affinity GTPase

Effect of 8-arginine vasopressin (AVP) was examined on human platelet membrane GTPase activity as an index of a G-protein involvement. AVP stimulated a high-affinity GTPase activity in a dose-dependent manner (Kact = 1.1 +/- 0.2 nM). This stimulation was blocked by a V1a antagonist, thus confirming the V1a nature of the platelet AVP receptor. There were important variations among individuals in the AVP-induced stimulation of GTPase activity, that were in relation with the AVP-maximal binding capacity. These data suggest a causal relationship between the binding of AVP to its receptor and transduction elicited by a G-protein, without amplification. In addition, in view of the variable AVP responsiveness observed among individuals, platelet AVP-receptor appears to be subject to regulation.     

Oxytocin in the periaqueductal grey regulates nociception in the rat

Studies have demonstrated that oxytocin (OXT) plays important roles in pain modulation in the central nervous system, and there are OXT receptors in the periaqueductal grey (PAG). The experiment was designed to investigate the effect of OXT in the PAG on antinociception. The results showed that (1) intra-PAG injection of OXT increased the pain threshold, whereas the local administration of the high specific OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold in a dose-dependent manner; (2) Pain stimulation could elevate OXT concentration in the PAG perfusion liquid. The data suggested that OXT in the PAG was involved in the antinociceptive process through the OXT receptor.     

Interactions of galanin with endomorphin-2, vasopressin and oxytocin in nociceptive modulation of the trigemino-hypoglossal reflex in rats

Galanin (GAL) is suggested to be a neuropeptide involved in pain transmission. In this study we tried to determine, whether the increase of GAL concentration in brain cells affects impulse transmission between the motor centers localized in the vicinity of the third and fourth cerebral ventricles. The experiments were carried out on rats under chloralose anesthesia. The study objectives were realized using the method allowing to record the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation during the perfusion of the cerebral ventricles with solutions containing tested compounds. Perfusion of the cerebral ventricles with GAL concentration-dependently inhibited the ETJ amplitude. The antinociceptive effect of GAL was blocked by a galanin receptor antagonist, galantide (GLT) and by opioid antagonists: non-selective naloxone (Nal) and micro-selective beta-funaltrexamine (beta-FNA). In contrast, a delta-opioid receptor antagonist, naltrindole (NTI) or the kappa-opioid receptor antagonist, nor-binaltrophimine (nor-BNI) did not inhibit the effect of GAL. The antinociceptive effect of GAL was more pronounced when GAL was perfused in combination with other neuropeptides/neurohormones, such as endomorphin-2 (EM-2), vasopressin (AVP) and oxytocin (OT). The present results demonstrate that in the orofacial area analgesic activity is modulated by GAL, OT and AVP and that EM-2-induced antinociception involves GAL.     

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the caudate nucleus to participate in pain modulation

Arginine vasopressin (AVP), which is synthesized and secreted in the hypothalamic paraventricular nucleus (PVN), is the most important bioactive substance in the pain modulation. Our pervious study had shown that AVP plays an important role in pain modulation in caudate nucleus (CdN). The experiment was designed to investigate the source of AVP in CdN by the nucleus push-pull perfusion and radioimmunoassay. The results showed that: (1) pain stimulation increased the AVP concentration in the CdN perfusion liquid, (2) PVN decreased the effect of pain stimulation which was stronger in both sides than in one side of PVN cauterization; and (3) L-glutamate sodium would excited the PVN neurons by the PVN microinjection that could increase the AVP concentration in the CdN perfusion liquid. The data suggested that AVP in the CdN might come from the PVN in the pain process, i.e., AVP in the PVN might be transferred to the CdN to participate in the pain modulation.     

弧束核参与剌激下丘脑室旁核的镇痛作用

This study was undertaken to evaluate the analgesic effect of paraventricular nucleus (PVN) stimulation with tail stimulation-vocalization test. The mechanism of this analgesia was analysed with nuclear lesion and microinjection technique. The main results were as follows: (1) Electrical stimulation of the PVN could significantly enhance the pain threshold and increase the content of AVP in brainstem measured by radioimmunoassay. (2) Solitary tract nucleus (STN) lesion could eliminate the analgesic effect induced by PVN stimulation. (3) Intranuclear microinjection of AVP-antagonist and AVP-antiserum into the STN could block the analgesic effect of PVN stimulation. (4) Intranuclear microinjection of AVP into the STN could mimick the analgesic effect similar to that of PVN stimulation. These results suggest that electrical stimulation of the PVN could produce an analgesic effect. This effect might be mediated by the activation of VP-ergic neurons in PVN and upon releasing VP from the descending fibers, the activities of neurons in the STN are influenced.     

Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.     

Effect of microinjections of 5-hydroxytryptamine and adrenaline in central grey on pain responsiveness during acute food deprivation in conscious rats

To study the effects of microinjections of 5 hydroxytryptamine and adrenaline in central grey on pain responsiveness during acute food deprivation, experiments were conducted in nine male rats. Microinjections of 5 HT (10 micrograms/microliter) and adrenaline (10 micrograms/microliter) were given in central grey before and at the end of 6, 12, 18 and 24 hr food deprivation and the effects on pain threshold, cardiorespiratory parameters and body temperature were noted. Observations showed that 5 HT increased the pain threshold (antinociception) significantly (P < 0.05) with no change in cardiorespiratory response and body temperature, adrenaline did not alter pain threshold with no change in cardiorespiratory response and body temperature. The observations suggest the possible existence of two types of monoaminergic receptors or pathways in the central grey.     

Interleukin 2-induced antinociception partially coupled with mu receptor

The present study was designed to investigate the involvement of mu receptor in interleukin 2-induced antinociception. Intraplantar injection of human recombinant interleukin 2 (rIL-2) (1. 5x10(4) U) significantly enhanced pain threshold as measured by paw withdrawal latencies (PWLs) to noxious radiant heat in normal rats. After administration of rIL-2, PWLs were also markedly increased in morphine-tolerant and chronic constriction injury (CCI)-operated rats, which have been proven morphine-insensitive. rIL-2-induced antinociception in both morphine-tolerant and CCI-operated rats was significantly lower than that in normal rats. rIL-2 antinociception was partially blocked by naloxone (1 mg/kg i.p.) in normal rats but remained unchanged in the CCI group. Our results suggest that the use of rIL-2 in human medical practice may be extended for its effectiveness in relief of neuropathic pain induced by CCI. Here we infer that mu receptor plays an critical role in IL-2-induced antinociception and that there are also some other receptors involved in this process.