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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In his programmatic paper published 1989 in this journal, Herbert Weiner held the view that psychosomatic medicine has become a medicine of human relations. The aim of this review is to reflect if current scientific evidence supports his view. Evidence from animal studies suggests that early infant-mother separation or neglect not only has a lasting influence on attachment behaviour, but also on brain development and the ability for stress regulation mediated by environmental as well as genetic factors. Neuronal networks processing affective components of physical pain play a role in signalling painful emotional experiences due to social isolation and separation. A consistent finding across different studies is that physicians who adopt a warm, friendly and reassuring manner help activate patients endogenous opioid system, foster their compliance and promote better therapeutic results. In summary, evidence from neurobiological studies not only support Herbert Weiner's theses but also opens new venues for interdisciplinary research.
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PMID:["A medicine of human relationship" revisited--Current neurobiological and psychosomatic developments]. 1755 79

Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.
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PMID:Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. 1766 59

Central pain following traumatic brain injury (TBI) has not been studied in depth. Our purpose was to conduct a systematic study of patients with TBI suffering from chronic central pain, and to describe the characteristics of the central pain. Groups were TBI patients with (TBIP) and without central pain (TBINP) and healthy controls. TBI patients with other pain mechanisms were excluded from the study. Participants underwent quantitative somatosensory testing in the painful and pain-free body regions. Thresholds for warmth, cold, heat-pain, touch and graphesthesia were measured and pathologically evoked pain (allodynia, hyperpathia and wind-up pain) evaluated. Chronic pain was mapped and characterized. Chronic pain developed at a relatively late onset (6.6+/-9 months) was almost exclusively unilateral and reported as pricking, throbbing and burning. Although both TBIP and TBINP exhibited a significant reduction in thermal and tactile sensations compared to controls, thermal sensations in the painful regions of TBIP were significantly more impaired than pain-free regions in the same patients (p<0.01) and in TBINP (p<0.01). Painful regions also exhibited very high rates of allodynia, hyperpathia and exaggerated wind-up. The characteristics of the chronic pain resembled those of other central pain patients although TBIP displayed several unique features. The sensory profile indicated that damage to the pain and temperature systems is a necessary but not sufficient condition for the development of chronic central pain following TBI. Neuronal hyperexcitability may be a contributing factor to the chronic pain.
Pain 2007 Oct
PMID:The characteristics of chronic central pain after traumatic brain injury. 1770 88

Pain intensity in chronic venous disease varies with the stage in the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification but also with patient perception, pain being by definition subjective. The venous hypertension responsible for the varicose veins and trophic changes in CVD has a variety of algogenic repercussions in which leukocytes play a particular role, notably through their ability to roll along the vessel wall. Shear stress, hypoxia and stasis activate the marginated leukocytes to shed L-selectin from their surface and express integrins, matrix metalloproteinase 9, elastase, lactoferrin and free radicals. Meanwhile the endothelium expresses adhesion molecules that permit slow rolling on E-selectin followed by adhesion and tissue transmigration. Vein wall and valve areas in particular attract mast cells, monocyte-macrophages and T lymphocytes, and undergo remodeling. Sympathetic sensory C and Adelta fibers, which wrap around cutaneous venules and are also present in the venous intima and media, are nociceptors sensitive to the pain mediators concentrated within leukocytes, such as mast cell bradykinin, responsible for visceral pain. Neuronal inflammation combined with wall remodeling intensifies symptoms. Yet no direct link has so far been shown between pain and mast cell mediator levels. Leukocyte adhesion is also associated with the increased capillary permeability that leads to edema. Antileukocyte therapies include postural rest and venotonics which alone or in combination with compression have been shown to unstick and inhibit leukocytes. The micronized purified flavonoid fraction (MPFF) protects vascular endothelium against hypoxia and reduces adhesion molecule expression. Unlike other antileukocyte therapies, venotonics do not cause neutropenia.
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PMID:Leukocyte involvement in the signs and symptoms of chronic venous disease. Perspectives for therapy. 1772 58

Modulation of spinal nociception from the anterior hypothalamus/preoptic area (AH/POA), and consequent alterations in the pain experience may contribute to integrated responses brought into play during fear or stress and as part of the sickness response. This study was designed to compare the effects of descending control from AH/POA on A- versus C-fibre-evoked spinal nociception, since any differential control is of behavioural and clinical importance given that A-fibre and C-fibre nociceptors convey different qualities of the pain signal (first and second pain, respectively), and play different roles in the development and maintenance of chronic pain states. In anaesthetised rats, electromyographic responses were recorded to monitor thresholds of withdrawal to slow (2.5 degrees Cs(-1)) or fast (7.5 degrees Cs(-1)) rates of skin heating of the hindpaw, to preferentially activate C- or A-nociceptors, respectively. Neuronal activation by microinjection of dl-homocysteic acid at sites within a specific region of AH/POA, lateral area of the anterior hypothalamus (LAAH), significantly increased response thresholds to slow heating rates (p<0.02, n=11), but not those to fast rates of heating (p=0.48, n=10). Injection of DLH adjacent to LAAH (n=9) had no significant effect on responses to slow (n=8) or fast (n=9) rates of skin heating. The functional significance of differential descending control of spinal processing of C- and A-nociceptive inputs is discussed with respect to roles both of the LAAH in pain processing, and of C- and A-nociceptive inputs in acute and chronic pain.
Pain 2008 Jun
PMID:Selective inhibition from the anterior hypothalamus of C- versus A-fibre mediated spinal nociception. 1782 51

Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 microg/5 microl) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mechanical hypersensitivity on day 7 post-nerve injury in wildtype mice. Intrathecal injection of 7-nitroindazole (8.15 microg/5 microl), a selective nNOS inhibitor, also dramatically attenuated nerve injury-induced mechanical hypersensitivity. Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.
Mol Pain 2007 Oct 08
PMID:Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice. 1792 9

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.
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PMID:Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain. 1793 54

This study was designed to shed more light onto the three different brainstem regions which are implicated in the pain pathway for the level of various excitatory and inhibitory neurotransmitters before and following neuronal stimulation. The in vivo microdialysis technique was used in awake, freely moving adult Sprague-Dawley rats. The neurotransmitters studied included aspartate, glutamate, GABA, glycine, and taurine. The three brainstem regions examined included the mid-brain periaqueductal gray (PAG), the medullary nucleus raphe magnus (NRM), and the spinal trigeminal nucleus (STN). Neuronal stimulation was achieved following the administration of the sodium channel activator veratridine. The highest baseline levels of glutamate (P < 0.0001), aspartate (P < 0.0001), GABA (P < 0.01), taurine (P < 0.0001), and glycine (P < 0.001) were seen in the NRM. On the other hand, the lowest baseline levels of glutamate, GABA, glycine, and taurine were found in the PAG, while that of aspartate was found in the STN. Following the administration of veratridine, the highest release of the above neurotransmitters except for the aspartate and glycine was found in the PAG where the level of glutamate increased by 1,310 +/- 293% (P < 0.001), taurine by 1,008 +/- 143% (P < 0.01), and GABA by 10,358 +/- 1,920% (P < 0.0001) when comparison was performed among the three brainstem regions and in relation to the baseline levels. The highest release of aspartate was seen in the STN (2,357 +/- 1,060%, P < 0.001), while no significant difference was associated with glycine. On the other hand, the lowest release of GABA and taurine was found in the STN (696 +/- 91 and 305 +/- 25%, respectively), and glutamate and aspartate in the NRM (558 +/- 200 and 874 +/- 315%, respectively). Our results indicate, and for the first time, that although some differences are seen in the baseline levels of the above neurotransmitters in the three regions studied, there are quite striking variations in the level of release of these neurotransmitters following neuronal stimulation in these regions. In our opinion this is the first study to describe the pain activation/modulation related changes of the excitatory and inhibitory amino acids profile of the three different brainstem areas.
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PMID:A comparative study of excitatory and inhibitory amino acids in three different brainstem nuclei. 1794 Aug 99

Nerve injury can lead to mechanical hypersensitivity in both humans and animal models, such that innocuous touch produces pain. Recent functional studies have demonstrated a critical role for descending pain-facilitating influences from the rostral ventromedial medulla (RVM) in neuropathic pain, but the underlying mechanisms and properties of the relevant neurons within the RVM are essentially unknown. We therefore characterized mechanical responsiveness of physiologically characterized neurons in the RVM after spinal nerve ligation, a model of neuropathic pain that produces robust mechanical hyperalgesia and allodynia. RVM neurons were studied 7-14 d after spinal nerve ligation, and classified as "on-cells," "off-cells," or "neutral cells" using standard criteria of changes in firing associated with heat-evoked reflexes. On-cells are known to promote nociception, and off-cells to suppress nociception, whereas the role of neutral cells in pain modulation remains an open question. Neuronal and behavioral responses to innocuous and noxious mechanical stimulation were tested using calibrated von Frey filaments (4-100 g) applied to the hindpaws ipsilateral and contralateral to the injury, and in sham-operated and unoperated control animals. On- and off-cells recorded in nerve-injured animals exhibited novel responses to innocuous mechanical stimulation, and enhanced responses to noxious mechanical stimulation. Neuronal hypersensitivity in the RVM was correlated with behavioral hypersensitivity. Neutral cells remained unresponsive to cutaneous stimulation after nerve injury. These data demonstrate that both on- and off-cells in the RVM are sensitized to innocuous and noxious mechanical stimuli after nerve injury. This sensitization likely contributes to allodynia and hyperalgesia of neuropathic pain states.
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PMID:Sensitization of pain-modulating neurons in the rostral ventromedial medulla after peripheral nerve injury. 1804 16

Neuronal nicotinic receptors are the subject of intensive research focused on developing novel therapies for drug abuse, neurocognitive disorders, neurodegenerative diseases, and pain. In this study, we have applied pharmacological magnetic resonance imaging (phMRI) in awake rats to map functional brain responses to the selective alpha(4)beta(2) nicotinic receptor agonists, A-85380, and ABT-594. Moreover, we have validated our methods by comparison with autoradiography using [(3)H]-A-85380 and [(3)H]-ABT-594. Under awake conditions (no anesthesia during scanning) where rats were habituated to the imaging environment, both compounds increased regional cerebral blood volume (rCBV) across multiple brain regions that closely matched regional brain receptor distribution with the same tritiated compounds. In addition, regional ABT-594-induced rCBV changes under awake conditions were also derived and characterized using a pharmacological model. Area-under-curve and maximum rCBV changes in brain were found to be dose-related and region-specific, and corresponded well with the known preclinical behavioral profile of this drug. In contrast, under conditions of alpha-chloralose anesthesia where physiological variables were maintained within normal ranges, increases in rCBV induced by ABT-594 were primarily restricted to some cortical areas and did not agree well with autoradiography data. Our data demonstrate the utility of using phMRI in awake animals to characterize selective pharmacological action but also highlight an important confound (anesthesia) that is rarely considered in preclinical phMRI studies.
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PMID:Pharmacological MRI in awake rats predicts selective binding of alpha4beta2 nicotinic receptors. 1808 Nov 83


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