Control of pituitary secretion of melanotropin in an anuran amphibian by thyrotropin releasing factor (TRH). Study in vitro]

Intermediate lobes from Rana esculenta pituitary glands were continuously superfused for 7 hrs at 28 degrees C with amphibian culture medium. alpha-MSH release was measured by use of a sensitive double antibody radio-immunoassay system. alpha-MSH secretion was inhibited by low temperatures. A large increase in alpha-MSH release was observed when Thyrotropin Releasing Hormone (TRH) at doses ranging from 10(-9) to 10(-7) molar was added to the superfusion medium. Since large amounts of TRH are to be found in the hypothalamus of amphibians but have no effect over pituitary TSH secretion, the action of TRH over alpha-MSH release may have a physiological significance.     

Antidiuretic hormone involvement in the release of alpha-melanocyte-stimulating hormone by hyperosmotic stimuli

In the normal Wistar rat, the plasma alpha-MSH level was raised by hypertonic saline injection (as compared with control rats injected with isotonic saline). No such rise in alpha-MSH followed hypertonic saline administration in the Brattleboro (hereditary diabetes insipidus) animal (compared to isotonic saline injected controls). It is suggested that, in the rat, endogenous antidiuretic hormone is involved in the secretory response of the pars intermedia to osmotic stimuli.     

Influence of alpha-MSH and ACTH on cortical bone remodelling in hypophysectomized rats.

Hypophysectomy increases both periosteal resorption and endosteal apposition along the femur diaphysis in rat. Administration of alpha-MSH decreased the periosteal resorption but had no effect on the endosteal apposition. ACTH had only minor effects on the endosteum. Thus, alpha-MSH and ACTH, in the doses used, have different effects on cortical bone in rat. The effect of alpha-MSH on cortical bone could be an effect of the hormone alone or by its stimulation of other factors.     

Immunofluorescence identification of cells with corticotropic and alpha-melanotropic activity in the hypophysis of the grass snake Natrix natrix L.]

The use of anti ACTH (17-39) and alpha-MSH allowed us to detect by immunofluorescence in the Pituitary gland of Grass Snake the site of elaboration of ACTH and alpha-MSH. Corticotropic cells are located in the rostral part of the Pars Distalis and in the Pars intermedia. Melanotropic cells occupy the whole part of the Pars intermedia.     

Immunocytological identification of two cell types in the intermediate lobe of the hypophysis of salmonids: presence of ACTH and alpha-MSH]

The lead-haematoxylin positive cells (PbH+) of the rostral pars distalis react with antibodies anti-1-24 ACTH and anti-17-39 ACTH; the pars intermedia (PI) is composed of two cell categories, but only one is revealed with cyto-immunological techniques and contains ACTH and alpha-MSH in several Salmonid species.     

Distribution of thyrotropin releasing hormone (TRH), alpha-melanocyte-stimulating hormone (alpha-MSH) and somatostatin in the skin of the green frog (Rana esculenta)]

High concentrations of Thyrotrophin-Releasing Hormone (TRH) have been found in the dorsal skin of the Frog Rana esculenta, lower levels being measured in the ventral skin. alpha-MSH and somatostatin were undetectable in these tissues. Nor was TRH detected in the blood of these animals. The concentration of somatostatin in the pancreas was similar to that of the hypothalamus and twice or one hundred times higher than in the intestine or stomach respectively.     

Immunohistochemical study of the pars intermediate of the mouse pituitary in different experimental conditions.

Alpha-MSH, beta-MSH and ACTH have been localized in the cells of hypophyseal intermediate lobe by fluorescence histoimmunological technics. Elaboration and excretion of these polypeptides are enhanced after dehydration or adrenalectomy. The most evident variations are seen with alpha-MSH and ACTH after dehydration, with beta-MSH after adrenalectomy.     

Endocrine cells producing regulatory peptides

Recent data on the immunolocalization of regulatory peptides and related propeptide sequences in endocrine cells and tumors of the gastrointestinal tract, pancreas, lung, thyroid, pituitary (ACTH and opioids), adrenals and paraganglia have been revised and discussed. Gastrin, xenopsin, cholecystokinin (CCK), somatostatin, motilin, secretin, GIP (gastric inhibitory polypeptide), neurotensin, glicentin/glucagon-37 and PYY (peptide tyrosine tyrosine) are the main products of gastrointestinal endocrine cells; glucagon, CRF (corticotropin releasing factor), somatostatin, PP (pancreatic polypeptide) and GRF (growth hormone releasing factor), in addition to insulin, are produced in pancreatic islet cells; bombesin-related peptides are the main markers of pulmonary endocrine cells; calcitonin and CGRP (calcitonin gene-related peptide) occur in thyroid and extrathyroid C cells; ACTH and endorphins in anterior and intermediate lobe pituitary cells, alpha-MSH and CLIP (corticotropin-like intermediate lobe peptide) in intermediate lobe cells; met- and leu-enkephalins and related peptides in adrenal medullary and paraganglionic cells as well as in some gut (enterochromaffin) cells; NPY (neuropeptide Y) in adrenaline-type adrenal medullary cells, etc.. Both tissue-appropriate and tissue-inappropriate regulatory peptides are produced by endocrine tumours, with inappropriate peptides mostly produced by malignant tumours.     

Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain

Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron–glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.     

The glycinergic control of spinal pain processing

Alterations in synaptic transmission within the spinal cord dorsal horn play a key role in the development of pathological pain. While N-methyl-D-aspartate (NMDA) receptors and activity-dependent synaptic plasticity have been the focus of research for many years, recent evidence attributes very specific functions to inhibitory glycinergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the generation of inflammatory and neuropathic pain. The central component of inflammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by the inflammatory mediator prostaglandin E₂ (PGE₂). PGE₂ activates prostaglandin E receptors of the EP2 subtype and leads to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors containing the α3 subunit (GlyRα3). This GlyRα3 is distinctly expressed in the superficial dorsal horn, where nociceptive afferents terminate. Other but probably very similar disinhibitory mechanisms may well contribute to abnormal pain occurring after peripheral nerve injury.Received 11 March 2005; received after revision 1 April 2005; accepted 19 April 2005     

Naloxone prevents the analgesic action of α-MSH in mice

Summary -MSH (0.1, 1, 10 g) was administered intracerebroventricularly and its action on pain sensitivity was investigated by the hot-plate method in mice. -MSH produced dose-dependent analgesia and this analgesic effect was prevented by naloxone (1 mg/kg, s.c.). It is possible that -MSH may play a role in the mechanism of pain through endogeneous opioid systems.     

Cortical modulation of pain

The sensation commonly referred to as pain has two components. The first is the sensory-discriminative component and provides information on location, modality and intensity of stimuli. The second is the affective-motivational component and refers to the emotional responses (fear, distress etc.) and the urge to respond evoked by the somatic sensation, and at the cortical level these two components appear to be located in different regions. The cortex probably influences pain by two different mechanisms. There is good evidence that the cortex can reduce pain by interrupting the transmission of noxious information from the spinal cord level by activating descending pain modulatory systems located in the brainstem. Less well established is the idea that modulation can also occur at the cortical level to change the affective-motivational aspects of nociception so that pain is perceived but looses its emotional and aversive component.Received 28 June 2004; received after revision 17 August 2004; accepted 21 August 2004     

Impact of neuropathic pain on the gene expression and activity of cytochrome P450side-chain-cleavage in sensory neural networks

Development of efficient therapy against chronic and stubborn pains requires fundamental identification of adequate cellular and molecular targets. This study combined cellular, molecular and biochemical approaches to investigate the gene expression and enzymatic activity of cytochrome P450side-chain-cleavage (P450scc) in spinal neural networks under normal and neuropathic pain states. P450scc is the key onset enzyme for steroidogenesis in endocrine glands and for neurosteroid biosynthesis in nerve cells. The P450scc gene was over-expressed in spinal and supra-spinal networks during neuropathic pain provoked by sciatic nerve ligature. Plasticity was observed in P450scc cellular distribution in pain circuits and its activity also increased inducing in vivo, hyper-secretion of pregnenolone and allopregnanolone which strongly stimulates type A receptors for g-aminobutyric acid, a pivotal neurotransmitter involved in pain modulation. These results, by establishing a direct link between neuropathic pain and neuroactive steroid formation in the nervous system, open new perspectives for chronic-pain modulation by endogenous neurosteroids.Received 8 June 2004; received after revision 2 July 2004; accepted 13 July 2004     

Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice

Neuropathic pain is a very complex disease, involving several molecular pathways. Current available drugs are usually not acting on the several mechanisms underlying the generation and propagation of pain. We used spared nerve injury model of neuropathic pain to assess the possible use of human mesenchymal stem cells (hMSCs) as anti-neuropathic tool. Human MSCs were transplanted in the mouse lateral cerebral ventricle. Stem cells injection was performed 4 days after sciatic nerve surgery. Neuropathic mice were monitored 7, 10, 14, 17, and 21 days after surgery. hMSCs were able to reduce pain-like behaviors, such as mechanical allodynia and thermal hyperalgesia, once transplanted in cerebral ventricle. Anti-nociceptive effect was detectable from day 10 after surgery (6 days post cell injection). Human MSCs reduced the mRNA levels of the pro-inflammatory interleukin IL-1β mouse gene, as well as the neural β-galactosidase over-activation in prefrontal cortex of SNI mice. Transplanted hMSCs were able to reduce astrocytic and microglial cell activation.     

The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR. These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein 1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism. Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength. Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms independent of NMDAR.     

Central mechanisms of experimental and chronic neuropathic pain: Findings from functional imaging studies

Over the last few years remarkable efforts have been made using functional imaging studies to unravel brain processing of pain and decipher underlying neuronal mechanisms. Cerebral processing in experimental pain models, especially those provoking hyperalgesia, and its pharmacological modulation will form the first part of this review. In a second part we will address central mechanisms of clinical neuropathic pain. Up to now, there are at least six main mechanisms involved in the chronification of neuropathic pain: (i) activity increase in areas of the pain neuromatrix, (ii) recruitment of additional cortical areas beyond the classical pain neuromatrix, (iii) cortical reorganization and maladaptive neuroplasticity, (iv) alterations in neurochemistry (v) structural brain changes and (vi) disruption of the brain default mode network. In a third part of this review we discuss mechanisms of endogenous pain modulation. Received 22 July 2008; received after revision 26 August 2008; accepted 2 September 2008     

聚焦超声辐照右足三里对痛阈的影响

目的观察聚焦超声辐照正常人右足三里对痛闽的影响。方法40例正常健康人,随机分成聚焦超声辐照组和安慰剂对照组,各20例。聚焦超声辐照右足三里30min,用Electronic Von Frey测定机械痛阈。在聚焦超声辐照前和开始辐照后10、20、30、40、50、60min记录机械痛阈。安慰剂对照组同时进行对比测量。结果超声辐照组,辐照前后左右两侧痛阈值分别有显著性差异（P〈0.01）;对照组,辐照前后左右两侧痛阈值均无统计学意义（左侧P=0．904,右侧P=0．274）。超声辐照组相邻时间水平有显著差异（P〈0．01）,对照组相邻时间水平无显著差异;左右两侧不同部位间无显著性差异（P=0．176）;时间与部位无交互效应（P=0．411）。结论聚焦超声辐照单侧足三里后痛阈明显升高,从而具有一定的镇痛作用。     

Glycine receptors and glycine transporters: targets for novel analgesics?

Glycinergic neurotransmission has long been known for its role in spinal motor control. During the last two decades, additional functions have become increasingly recognized—among them is a critical contribution to spinal pain processing. Studies in rodent pain models provide proof-of-concept evidence that enhancing inhibitory glycinergic neurotransmission reduces chronic pain symptoms. Apparent strategies for pharmacological intervention include positive allosteric modulators of glycine receptors and modulators or inhibitors of the glial and neuronal glycine transporters GlyT1 and GlyT2. These prospects have led to drug discovery efforts in academia and in industry aiming at compounds that target glycinergic neurotransmission with high specificity. Available data show promising analgesic efficacy. Less is currently known about potential unwanted effects but the presence of glycinergic innervation in CNS areas outside the nociceptive system prompts for a careful evaluation not only of motor function, but also of potential respiratory impairment and addictive properties.     

Deciphering microRNA code in pain and inflammation: lessons from bladder pain syndrome

MicroRNAs (miRNAs), a novel class of molecules regulating gene expression, have been hailed as modulators of many biological processes and disease states. Recent studies demonstrated an important role of miRNAs in the processes of inflammation and cancer, however, there are little data implicating miRNAs in peripheral pain. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. BPS is a chronic inflammatory condition that might share some of the pathogenetic mechanisms with its common co-morbidities inflammatory bowel disease (IBD), asthma and autoimmune diseases. Using miRNA profiling in BPS and the information about validated miRNA targets, we delineated the signaling pathways activated in this and other inflammatory pain disorders. This review projects the miRNA profiling and functional data originating from the research in bladder cancer and immune-mediated diseases on the BPS-specific miRNAs with the aim to gain new insight into the pathogenesis of this enigmatic disorder, and highlighting the common regulatory mechanisms of pain and inflammation.