Neuroendocrine pathway involvement in the loss of the cutaneous pressure-induced vasodilatation during acute pain in rats

Pain is regarded as a risk factor in pressure ulcer development by contributing to immobility. Pressure-induced vasodilatation (PIV) is a mechanism whereby cutaneous blood flow increases in response to progressive locally applied pressure, thereby delaying the occurrence of ischaemia and appearing to be a protective response to local pressure. When the interaction between nervous and vascular systems is deregulated, PIV, which relies on both systems, is absent. We thus hypothesized that acute pain could alter PIV. This study investigated the effects on PIV of acute pain triggered by noxious heat (50°C) applied to the tail of anaesthetized rats. To address the mechanisms underlying these effects, chronic sympathectomy was performed using guanethidine, and the plasma concentrations of pituitary adrenocorticotrophin (ACTH) and catecholamines were measured. Our results show that acute pain induces a loss of PIV associated with an increase of ACTH. Direct involvement of hypertensive effects and peripheral sympathetic nervous system are excluded in the loss of PIV, whereas the activation of brain structures that have descending inhibitory control cannot be excluded. A low dose of systemic morphine prevented this loss of PIV and maintained the ability of the cutaneous microcirculation to adapt to the applied pressure. The loss of a protective response to local pressure (PIV) induced by acute pain lends physiological support to the direct involvement of pain in pressure ulcer development. Therefore, an adequate evaluation and treatment of pain is crucial.     

Evidence for a preferential involvement of M1 muscarinic receptors in representational memory

The effects of intrahippocampal injections to the M1-selective antagonist pirenzepine and the M2-selective antagonist AF-DX 116 were examined on performance of a representational memory task in rats. Although both antagonists impaired performance, pirenzepine was more potent than AF-DX 116. Pirenzepine (70.8 +/- 2.8% correct) produced a greater deficit than AF-DX 116 (83.3 +/- 0.0%) at 70 micrograms, and the deficit at 10 micrograms (83.3 +/- 2.8%) was equal to that produced by 70 micrograms of AF-DX 116. The data provide additional support for the cholinergic hypothesis of memory and new information regarding the subtypes of muscarinic receptors likely to be involved in representational memory. Based on the greater susceptibility of representational memory to the effects of pirenzepine, it is suggested that M1 receptors in the hippocampus play a greater role in memory function than M2 receptors.     

Evidence for the involvement of receptors for fibronectin in the promotion of chick tail segmentation

Summary In the chick embryo the paraxial mesoderm forms about 50–53 pairs of somites, the precise number depending on the extent to which segmentation proceeds along the tail. However, the terminal mesoderm of the tail fails to segment despite the fact that it appears to contain a reservoir of potential somites. Why does this mesoderm not segment? Some clues can be obtained by comparing this non-segmenting region with the segmental plate in the trunk. We and others have shown that in the trunk region of the chick, cell adhesion plays a major role in somitogenesis and that this increased cell adhesion is associated with compaction of segments of mesoderm immediately prior to segmentation. This compaction can be brought about prematurely by fibronectin and by the specific adhesion peptide GRGDS. The terminal mesoderm in the tail resembles the segmental plate mesoderm in the trunk in undergoing compaction in response to fibronectin and GRGDS. The tail mesoderm differs from the segmental plate mesoderm in that it can also respond to peptides closely related to GRGDS. The response suggests that, whereas the integrin receptors for fibronectin and GRGDS appear to be specific in the presomitic trunk mesoderm, responding only to the specific adhesion-peptide GRGDS, the tail mesoderm may contain more heterogeneous sets of receptors within the integrin/VLA family that respond to a wider variety of ligands. Coincident with these differences is the phenomenon of regional cell death in the tail bud mesoderm. All of these factors are thought to play a role in the extent of segmentation in the paraxial mesoderm of the embryonic chick.     

Lack of interaction between etifoxine and CRF1 and CRF2 receptors in rodents

Hyperactivity of the corticotropin-releasing factor (CRF) system occurs in some patients with anxiety disorders and depression. Blockade of CRF1 and CRF2 receptors can underlie the anxiolytic effects of drugs. In the present investigation, in vivo and in vitro studies were designed to determine whether the anxiolytic drug etifoxine, known to enhance GABAergic synaptic transmission, behaves also as a CRF1 and CRF2 receptor antagonist. A drug exerting multiple actions may be of clinical interest in the treatment of various different forms of mood disorders. Using two animal models, it was found that etifoxine reversed the excess CRF-induced grooming but not the hypo-locomotion of the rat placed in an open field. Etifoxine attenuated the CRF-induced gastric emptying delay in the mouse. On the other hand, in vitro, binding of etifoxine to CRF1 and CRF2 receptors on rat brain membranes was negligible and functionally, etifoxine did not block the CRF1 and CRF2 activation-induced cAMP production in presence of CRF in human neuroblastoma SH-SY5Y cells. The selective anxiolytic properties of etifoxine appear unrelated to an antagonist activity at the CRF1 and CRF2 receptors. The decrease in CRF activity produced by etifoxine may be related to its GABAergic properties.     

Evidence for the involvement of kainate receptors in synaptic transmission in the avian cochlear nucleus

Previous studies using various excitatory amino acid antagonists have shown that synaptic transmission between the auditory nerve and the cochlear nucleus of chickens (nuc. magnocellularis; NM) is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors. In the present study we have attempted to define the subclass of non-NMDA receptor in the NM by examining the effects of various excitatory amino acid agonists on synaptically evoked field potentials in an in vitro preparation of the chicken brain stem. Both quisqualate and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), whose actions operationally define the quisqualate receptor class, caused variable and weak depression of evoked responses in the NM, as did L-glutamate. Kainic acid, on the other hand, completely blocked postsynaptic responses at micromolar concentrations. We conclude that kainate-preferring non-NMDA receptors play a predominant role in mediating transmission in the NM.     

Evidence for involvement of GNB1L in autism

Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5?Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P?=?0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well.     

Evidence for an involvement of NMDA and non-NMDA receptors in synaptic excitation of phrenic motoneurons in the rabbit

The action of endogenous excitatory amino acids on phrenic motoneurons was studied in anesthetized, vagotomized, paralyzed and artificially ventilated rabbits. The NMDA receptor antagonists APV and ketamine, as well as the non-NMDA receptor antagonists GAMS and DNQX were administered by microinjection into the ventral horn of the spinal segments C3-C5. Injection of each antagonist resulted in a reversible reduction of the phrenic nerve activity. Results suggest an important function of endogenous excitatory amino acids in the excitation of phrenic motneurons. NMDA as well as non-NMDA receptors are involved. The functional role of both receptor types in bulbospinal neurotransmission is discussed.     

Evidence for involvement of 5-HT2 and 5-HT1C receptors in the behavioral effects of the 5-HT agonist 1-(2,5-dimethoxy-4-iodophenyl aminopropane)-2 (DOI)

DOI (1-(2,5-dimethoxy-4-iodophenyl aminopropane)-2) has recently been suggested as a selective 5-HT2 receptor agonist, but its behavioral effects have not been previously reported. In naive rats, DOI induced dose-dependent shaking behavior, the novel behavior 'skin jerks' (paraspinal muscle contractions), and forepaw tapping of the 'serotonin syndrome'. These behaviors had a similar dose-response and time course and were blocked by the 5-HT2/5-HT1C antagonists mianserin, ritanserin, and methysergide. Skin jerks, unlike other behaviors, were not blocked by 1-propranolol or phenoxybenzamine, drugs with little activity at 5-HT2/5-HT1C sites. Differences in the pharmacology and neuroanatomy between skin jerks and shaking behavior suggest that the 5-HT1C receptor may participate in skin jerks and the 5-HT2 receptor in shaking behavior, but drug coaffinities for 5-HT2 and 5-HT1C receptors require further investigation.     

NK cell receptors in rodents and cattle

Natural killer (NK) cells discriminate between normal syngeneic cells and infected, neoplastic or MHC-disparate allogeneic cells. The reactivity of NK cells appears to be regulated by a balance between activating receptors that recognize non-self or altered self, and inhibitory receptors recognizing normal, self-encoded MHC class I molecules. Subfamilies of NK receptors undergo rapid evolution, and appear to co-evolve with the MHC. We here review present views on the evolution and function of NK cell receptors, with an emphasis on knowledge gained in cattle and rodents.     

Participation of beta receptors in reflex vasodilatation in the dog.

The effects of propranolol, given by direct intraarterial injection, on the reflex vasodilatation induced in the atropinized isolated gracilis muscle by rapid intravenous administration of norepinephrine, were studied in dogs. In these studies, both atropine and atropine plus propranolol did not significantly alter the maximum fall in vascular resistance in the perfused gracilis muscle following intravenous norepinephrine; however, if the reflex responses were evaluated as integrated areas of vasodilatation, atropine attenuated the vasodilatation and the administration of propranolol further attenuated the reflex. In fact, the value of the integrated areas of vasodilatation was 52.8 +/- 9 mmHg/min in the basal state, 39 +/- 6 mmHg/min after administration of atropine, and 24 +/- 7 mmHg/min after propranolol, whereas the integrated areas of the systemic hypertension did not show any modification. These results prompt us to conclude that the adrenergic beta receptors participate in the reflex vasodilatation, although the mechanism of their action needs further elucidation.     

Evidence for involvement of equine herpesvirus 1 glycoprotein B in cell-cell fusion

Summary Monoclonal antibodies specific for equine herpesvirus 1 (EHV-1) glycoproteins (gB, gD, gp2 and a cleaved translation product of gene 71) were tested for ability to inhibit cell-cell fusion as measured by syncytium formation in EHV-1 infected cell cultures. Syncytium formation was inhibited by a complement-dependent neutralising antibody (7B10) which recognised the large subunit of EHV-1 gB. This indicated that EHV-1 gB, in common with gB homologues of herpes simplex virus and other herpesviruses, plays a role in the cell-cell fusion process.     

Evidence for superantigen involvement in preeclampsia

PROBLEM: Preeclampsia is the leading cause of maternal morbidity and premature fetal delivery in the United States, most likely involving the immune system in disease genesis. In this report, we tested the hypothesis that a superantigen phenomenon is an important factor in the pathogenesis of the disease. METHOD OF STUDY: A semi-quantitative polymerase chain reaction (PCR) was used to assess T-cell receptor (TCR) beta chain variable (Vbeta) regions as an indicator of T-cell expansion in both peripheral blood and basal plate of preeclamptic patients. All the subjects were also molecularly typed to identify their HLA-class II alleles. RESULTS: In peripheral blood of the majority of the patients, there was a high abundance of the Vbeta4 gene family, which was not observed in the control group. Polyclonality of this Vbeta gene family was confirmed by analysis of the Valpha chain and the complementary determining region 3 (CDR3). The majority of patients carried the Human Leukocyte Antigens (HLA)-DRB1*13 allele. CONCLUSION: We present evidence for the existence of a superantigen-like effect in at least a subset of patients with preeclampsia.     

Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors

This study investigated the effect of adenosine in the forced swimming test (FST) and the tail suspension test (TST) in mice, and the contribution of adenosine A1 and A2A receptors to adenosine's antidepressant-like effect. The immobility time in the FST was reduced by adenosine given either by i.p. (5-10 mg/kg) or i.c.v. (0.01-10 microg/site) route. Adenosine (1-10 mg/kg, i.p.) also produced an antidepressant-like effect in the TST. No treatment affected locomotion in an open-field. The anti-immobility effect of adenosine (10 mg/kg, i.p.) in the FST was prevented by i.p. pretreatment of mice with caffeine (3 mg/kg), DPCPX (2 mg/kg) and ZM241385 (1 mg/kg). CHA (0.05 mg/kg, i.p.) and DPMA (1-5 mg/kg, i.p.) also produced an antidepressant-like effect in the FST. This is the first report of an antidepressant-like effect of adenosine in mice, apparently mediated through an interaction with A1 and A2A receptors.     

Evidence for the presence of D2 but not D1 dopamine receptors in rat hypothalamic perifornical area

Behavioural studies have shown that the perifornical hypothalamus (PFH) plays a fundamental role in mediating dopamine-induced anorexia. In the present report, we provide biochemical evidence for the occurrence of dopamine receptors in the PFH, but not in the paraventricular nucleus of the hypothalamus. Dopamine as well as bromocriptine, a D2 dopamine receptor agonist, strongly reduced the adenylate cyclase activity in the PFH. This inhibitory effect was reversed by haloperidol and by (-)-sulpiride, but not by (+)-sulpiride. On the contrary, the selective D1 dopamine agonist SKF 82526 was completely inactive in affecting adenylate cyclase activity. Our conclusion asserts the existence of dopamine D2 but not D1 receptors in the PFH, which therefore can be conceived as the only region in the brain where a single class of dopamine receptors is present.     

Evidence for involvement of group II/III metabotropic glutamate receptors in NMDA receptor-independent long-term potentiation in area CA1 of rat hippocampus

Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl-D-aspartate (NMDA) receptor-independent long-term potentiation (LTP) in area CA1 of the rat hippocampus. To learn more about the specific roles played by mGluRs in NMDA receptor-independent LTP, we used whole cell recordings to load individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5'-O-(2-thiodiphosphate), GDPbetaS]. Although loading postsynaptic CA1 pyramidal neurons with GDPbetaS significantly reduced G-protein dependent postsynaptic potentials, GDPbetaS failed to prevent NMDA receptor- independent LTP, suggesting that postsynaptic G-protein-dependent mGluRs are not required. We also performed a series of extracellular field potential experiments in which we applied group-selective mGluR antagonists. We had previously determined that paired-pulse facilitation (PPF) was decreased during the first 30-45 min of NMDA receptor-independent LTP. To determine if mGluRs might be involved in these PPF changes, we used a twin-pulse stimulation protocol to measure PPF in field potential experiments. NMDA receptor-independent LTP was prevented by a group II mGluR antagonist [(2S)-alpha-ethylglutamic acid] and a group III mGluR antagonist [(RS)-alpha-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group II and III mGluR antagonists [(RS)-alpha-methylserine-O-phosphate monophenyl ester or (RS)-alpha-methylserine-O-phosphate]. NMDA receptor-independent LTP was not prevented by either of the group I mGluR antagonists we examined, (RS)-1-aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The PPF changes which accompany NMDA receptor-independent LTP were not prevented by any of the group-selective mGluR antagonists we examined, even when the LTP itself was blocked. Finally, we found that tetanic stimulation in the presence of group III mGluR antagonists lead to nonspecific potentiation in control (nontetanized) input pathways. Taken together, our results argue against the involvement of postsynaptic group I mGluRs in NMDA receptor-independent LTP. Group II and/or group III mGluRs are required, but the specific details of the roles played by these mGluRs in NMDA receptor-independent LTP are uncertain. Based on the pattern of results we obtained, we suggest that group II mGluRs are required for induction of NMDA receptor-independent LTP, and that group III mGluRs are involved in determining the input specificity of NMDA receptor-independent LTP by suppressing potentiation of nearby, nontetanized synapses.     

Excitatory actions of vasoactive intestinal peptide on mouse thalamocortical neurons are mediated by VPAC2 receptors

Thalamic nuclei can generate intrathalamic rhythms similar to those observed at various arousal levels and pathophysiological conditions such as absence epilepsy. These rhythmic activities can be altered by a variety of neuromodulators that arise from brain stem regions as well as those that are intrinsic to the thalamic circuitry. Vasoactive intestinal peptide (VIP) is a neuropeptide localized within the thalamus and strongly attenuates intrathalamic rhythms via an unidentified receptor subtype. We have used transgenic mice lacking a specific VIP receptor, VPAC(2), to identify its role in VIP-mediated actions in the thalamus. VIP strongly attenuated both the slow, 2-4 Hz and spindle-like 5-8 Hz rhythmic activities in slices from wild-type mice (VPAC(2)(+/+)) but not in slices from VPAC(2) receptor knock-out mice (VPAC(2)(-/-)), which suggests a major role of VPAC(2) receptors in the antioscillatory actions of VIP. Intracellular recordings revealed that VIP depolarized all relay neurons tested from VPAC(2)(+/+) mice. In VPAC(2)(-/-) mice, however, VIP produced no membrane depolarization in 80% of neurons tested. In relay neurons from VPAC(2)+/+ mice, VIP enhanced the hyperpolarization-activated mixed cation current, I(h), via cyclic AMP activity, but VIP did not alter I(h) in VPAC(2)-/- mice. In VPAC(2)-/- mice, pituitary adenylate cyclase activating-polypeptide (PACAP) depolarized the majority of relay neurons via I(h) enhancement presumably via PAC(1) receptor activation. Our findings suggest that VIP-mediated actions are predominantly mediated by VPAC(2) receptors, but PAC(1) receptors may play a minor role. The excitatory actions of VIP and PACAP suggest these peptides may not only regulate intrathalamic rhythmic activities, but also may influence information transfer through thalamocortical circuits.     

Kinins, beta-adrenergic receptors and functional vasodilatation in the submaxillary gland of the cat

1. The close arterial infusion of bradykinin into the submaxillary gland of the cat produced a pronounced hyperaemia that could be blocked by simultaneous perfusion of the gland with blood containing carboxypeptidase B. Carboxypeptidase B, however, failed to reduce the vasodilatation of chorda tympani nerve stimulation suggesting that the kinins are not involved in the regulation of submaxillary gland blood flow.2. Isoproterenol injections produced pronounced salivary gland vasodilatation. Beta-adrenergic blocking drugs reduced or abolished the hyperaemia of isoproterenol and reduced that of chorda tympani nerve stimulation. The combination of beta-blocking drugs and atropine could abolish or reduce further this nerve induced hyperaemia.3. The above results suggest that stimulation of cholinergic and beta-adrenergic receptors could account for the chorda tympani induced hyperaemia. Conclusive proof of this possibility remains to be determined.     

Evidence for the role of dopamine D1 receptors in morphine induced stereotypic behavior

In the course of studying the effects of morphine on the escape from electrical stimulation to the rat medial forebrain bundle, we observed that a combination of low doses of morphine and stimulation, neither of which caused stereotypy in the rat, resulted in marked stereotypic behavior that was similar to that seen with high doses of morphine alone. This behavior could be blocked by either naloxone or by the D1 antagonist SCH 23390, but not by the D2 antagonist raclopride. Furthermore, the stereotypy caused by chronically administered high doses of morphine was blocked by naloxone and the D1 antagonist. These results strongly implicate the role of dopamine D1 activation in morphine-induced stereotypies.     

Evidence for opioid involvement in the motivation to sing

Songbirds produce high rates of song within multiple social contexts, suggesting that they are highly motivated to sing and that song production itself may be rewarding. Progress has been made in understanding the neural basis of song learning and sensorimotor processing, however little is known about neurobiological mechanisms regulating the motivation to sing. Neural systems involved in motivation and reward have been conserved across species and in songbirds are neuroanatomically well-positioned to influence the song control system. Opioid neuropeptides within these systems play a primary role in hedonic reward, at least in mammals. In songbirds, opioid neuropeptides and receptors are found throughout the song control system and within several brain regions implicated in both motivation and reward, including the medial preoptic nucleus (POM) and ventral tegmental area (VTA). Growing research shows these regions to play a role in birdsong that differs depending upon whether song is sexually motivated in response to a female, used for territorial defense or sung as part of a flock but not directed towards an individual (undirected song). Opioid pharmacological manipulations and immunocytochemical data demonstrate a role for opioid activity possibly within VTA and POM in the regulation of song production. Although future research is needed, data suggest that opioids may be most critically involved in reinforcing song that does not result in any obvious form of immediate externally mediated reinforcement, such as undirected song produced in large flocks or during song learning. Data are reviewed supporting the idea that dopamine activity underlies the motivation or drive to sing, but that opioid release is what makes song production rewarding.