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

Certain neuropathic pain states, including postherpetic neuralgia and trigeminal neuralgia, show a dramatically increased incidence in the aged. Two recent experimental observations, unrelated a priori, might provide insight into why this is so. The first observation appeared unexpectedly during the course of a quantitative morphometric study aimed at determining the kinetics of retrograde cell death in dorsal root ganglia (DRGs) of adult male rats after nerve injury. Although the expected falloff in the ratio of neurons on the operated side versus the contralateral intact side was confirmed, much of the change resulted from an increase in the number of cells on the intact side. DRG cell counts were then carried out in intact, unoperated rats of various ages, and an increase in neuronal populations with age and size was confirmed. However, as the rats entered "old age" (greater than 400 days of age), proliferation ceased and there was an indication of secondary cell loss (involution). This is consistent with other data on DRG involution in the aged. The second observation is that regressive changes in DRGs following nerve injury are associated with enhanced generation of ectopic impulse discharge in the DRG, and potentiated cross-excitation among neighboring DRG neurons. It is likely that these post-injury changes in DRG electrogenesis contribute to the neuropathic sensory abnormalities, including chronic pain, that are associated with traumatic nerve injury. Considering both observations together, it is possible that DRG involution in the aged triggers electrical changes in the DRG resembling those associated with DRG involution following nerve injury. If so, this process could account for the special susceptibility of elderly patients to certain neuropathic pain states.
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PMID:Chronic pain in the aged: possible relation between neurogenesis, involution and pathophysiology in adult sensory ganglia. 178 57

A long-term culture system of dissociated rat dorsal root (DRG) and trigeminal ganglion cells with high cell density has been developed. Two to 3 weeks after plating, the cultures consist of a nearly pure population of sensory neurons, which can be kept for more than 2 months in culture. Cultured neurons synthesize and release the tachykinins substance P (SP) and substance K (SK, neurokinin A) with a time course similar to that observed in vivo. High-pressure liquid chromatography (HPLC) analysis of peptides extracted from neuronal cultures and synthetic tachykinins revealed identical retention characteristics. Northern blot analysis of mRNAs from cultured cells with a specific tachykinin-probe demonstrated that the preprotachykinin-gene is expressed in preparations of both DRG and trigeminal ganglia cells. Depolarizing stimuli such as high potassium (47 mM) evoked a peptide release from cultured neurons in a strictly Ca(++)-dependent manner. Capsaicin, a compound known to stimulate nociceptive sensory neurons, dose-dependently released tachykinins in concentrations as low as 10(-9) M. Only total absence of Ca++ ions from the incubation medium abolished the capsaicin-induced peptide release. Nifedipine, a blocker of voltage-dependent L-type Ca++ channels, completely blocked the potassium-induced release of SP but did not reduce the capsaicin-evoked release. Mediator substances of pain and inflammation, such as bradykinin, serotonin, and histamine, triggered the release of tachykinins from sensory neurons in vitro. These results clearly demonstrate that the neurons characterized express properties similar to those of sensory neurons in vivo and provide model systems for detailed studies of the biosynthesis and release of neuropeptides as well as the participation of sensory neurons in pain and inflammatory reactions.
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PMID:Biosynthesis and release of tachykinins from rat sensory neurons in culture. 179 53

1. Experiments based on teased fiber recording from rat sciatic nerve have shown that a small proportion of primary afferent neurons in intact dorsal root ganglia (DRGs) fire spontaneously. The prevalence of this discharge is substantially increased if the sciatic nerve has been chronically injured. 2. We now show that in most cases this ongoing DRG activity can be augmented by tetanic stimulation of the axons of neighboring neurons, where the active neuron itself has not been stimulated. In addition, some previously silent DRG neurons can be cross-excited by neighbors. This novel form of neuron-to-neuron communication is termed "DRG crossed afterdischarge." Cross-excitation never occurred at fixed latency in response to single stimulus pulses and is therefore not a case of ephaptic cross talk. 3. Crossed afterdischarge occurred only if the spontaneously active neuron and the stimulated neighbors shared the same DRG. It occurred in 83.5% of the spontaneously active neurons sampled that had myelinated (A) axons, but in only 4.4% of spontaneously active neurons with unmyelinated (C) axons. Among initially silent neurons, stimulation of neighbors evoked firing in 3.1% of A-fibers but in no C-fibers. 4. Crossed afterdischarge responses began within 500 ms of stimulation onset (with the use of 50-Hz tetani) and increased in magnitude for about the first 30 s of stimulation, declining thereafter. Intense excitations were often followed by a short period of depression until the original rate of ongoing discharge was restored. 5. The magnitude of crossed afterdischarge responses increased with increasing stimulation frequency until saturation. Minimal responses occurred with the use of tetani of as little as 1 Hz. Maximal responses occurred with the use of 100-200 Hz tetani. 6. The inclusion of C-fibers in the afferent volley produced little if any augmentation of responses. 7. Cross-excitation was demonstrated in DRGs in which many or all peripheral afferent axons were intact and continued to innervate hind limb skin. In these preparations natural cutaneous stimulation was shown to be capable of evoking crossed afterdischarge responses. The most effective stimuli were gentle or firm rubbing of the foot. Noxious pinch, heat, cold, and chemical stimulation was ineffective. 8. DRG crossed afterdischarge is a mechanism whereby sensation in response to peripheral stimulation may be distorted in time, space, and modality. Because its prevalence is much increased after axotomy, it might contribute to neuropathic sensory abnormalities, including pain, in patients with nerve injury.
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PMID:Cross-excitation in dorsal root ganglia of nerve-injured and intact rats. 207 61

Anterogradely transported wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was used to selectively label the distribution within the guinea pig heart of cardiac sympathetic afferent fibers whose cell bodies lie in the dorsal root ganglia (DRGs) of C6, C8, T1-3. The majority of fibers were seen in the posterior atrial wall, the pulmonary arterial walls, and along the major branches of the coronary arteries. Labeled fibers were also found in the parietal pericardium and associated with the atrioventricular and aortic valves. The labeling pattern was dependent upon segmental level: the most general labeling followed upper thoracic DRG injection, while labeled fibers associated with the coronary arteries were nearly absent after lower cervical DRG injection. Comparison of heart labeling among chemically sympathectomized and untreated animals demonstrated no difference in the distribution of frequency of WGA-HRP labeled fibers, indicating the specificity of this technique. The present findings indicate that the spinal sensory innervation of the heart has its major origins in the uppermost thoracic dorsal root ganglia and has a highly selective regional distribution. The implications of these findings in relation to cardiac autonomic dysfunction and pain are discussed.
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PMID:Distribution of cardiac sympathetic afferent fibers in the guinea pig heart labeled by anterograde transport of wheat germ agglutinin-horseradish peroxidase. 314 48

Capsaicin is a pungent pain-producing compound found in plants of the capsicum family; it exerts excitatory, desensitizing, and toxic effects on a subset of sensory neurons, including the polymodal nociceptor population. We have carried out a quantitative study of capsaicin-induced fluxes of sodium, guanidine, calcium, rubidium, and chloride ions in cultures of neonatal and adult rat DRG neurons, in conjunction with the use of a histochemical stain that identifies capsaicin-sensitive neurons by means of cobalt uptake. Those cells that take up cobalt in a capsaicin-dependent manner (EC50 = 0.2 microM) represent about 50% of the total neuronal population derived from neonatal DRGs on short-term culture. Overnight treatment of cultures with 2 microM capsaicin leads to the loss of the cobalt-staining subpopulation. The capsaicin-insensitive neurons contain immunoreactive neurofilament epitopes that are present in fewer than 10% of capsaicin-sensitive neurons. This observation provides indirect evidence that the sensitive cells correspond to the small, dark B-type neurons, which are negative for neurofilament immunoreactivity in vivo. A capsaicin-dependent calcium uptake (EC50 = 0.2 microM), as measured by 45Ca incorporation, is shown by a DRG neuronal subpopulation that, like the cobalt-staining population of DRG neurons, is lost after overnight capsaicin treatment (2 microM). Capsaicin application leads to the accumulation of millimolar levels of calcium within a few minutes. Cadmium and other divalent cations block capsaicin-induced calcium uptake, but little or no inhibition is seen with organic calcium channel antagonists. Mitochondria, rather than the endoplasmic reticulum, are the probable destination of the internalized calcium, because ruthenium red inhibits calcium uptake (IC50 = 0.05 microM), whereas methylxanthines are inactive. The subset of sensory neurons that takes up calcium also releases 86Rb when exposed to capsaicin (EC50 = 0.06 microM). No efflux of 36Cl ions could be induced by capsaicin. These cells also show a capsaicin-induced uptake of 22Na or 14C guanidine (EC50 = 0.06 microM). In contrast, chick DRG cells in culture showed no capsaicin-induced calcium or cobalt uptake. Primary cultures of rat superior cervical ganglion neurons and Schwann cells, and a number of neuronal cell lines, also failed to respond to capsaicin, as judged by the calcium, cobalt, or guanidine uptake assays.
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PMID:Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. 317 75

Peripheral nerve injury may lead to a chronic neuropathic pain state that results from an increase in excitability of central neurons. This central sensitization is mediated via an N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). As NO is suggested to play a role in nociceptive transmission following nerve injury, we examined for altered NO synthase activity at multiple levels of peripheral and spinal neural tissue in a rat model of neuropathic pain. Peripheral neuropathy was induced in rats (N = 12) by ligation of the left L5 and L6 nerve roots. Six other rats had sham surgery. An ipsilateral decrease in paw withdrawal threshold to mechanical stimuli confirmed the presence of a neuropathic pain state. Samples of the lumbar and thoracic spinal cords, L4, L5, and L6 dorsal root ganglia (DRGs), and the sciatic nerves were obtained from the lesioned and contralateral sides at 2 and 4 weeks after neuropathic surgery (N = 6 per group). In the lumbar spinal cord, a bilateral decrease in nitric oxide synthase (NOS) activity was observed 2 and 4 weeks after neuropathic surgery. NOS activity was increased in the ipsilateral L5 and 6 DRGs 2 weeks following neuropathic surgery. An increase in NOS activity in the DRG may be an early mechanism for inducing more central changes. The bilaterally decreased NOS activity in the lumbar spinal cord may be secondary to a negative feedback mechanism resulting from increased NO production in the spinal dorsal root ganglia. Multiple alterations in expression of NOS activity that occur in both peripheral and central processing may play a role in the pain behavior resulting from peripheral nerve injury. (Preliminary results of these studies have been presented in abstract form at the annual meetings of the Society for Neuroscience, 1994, and the American Society of Anesthesiologists, 1994).
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PMID:Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue. 879 Dec 33

Nociceptors belong to A delta and C afferents that are equipped in the periphery with receptors for detecting potentially damaging physical and chemical stimuli. This review summarizes experimental evidence that these receptors represented by ionic channels are also functionally expressed on the cell bodies of sensory neurones in short-term cultures. The nociceptors belong predominantly to the small and medium size DRG neurones in which algogens such as weak acids, capsaicin, bradykinin and scrotonin produce inward currents that can generate impulse activity. It seems likely that the neurones which are not sensitive to algogens but to GABA, ATP or glutamate, agents not producing pain in humans, belong to other categories of DRG neurones equipped for detecting other modalities of sensation. new techniques for physical stimulation of DRG neurones in culture may be of great help in the search for complementing the criteria for distinguishing nociceptors among other neurones in culture. It is suggested that such an in vitro model will be useful for studying cellular mechanisms of nociception.
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PMID:Can sensory neurones in culture serve as a model of nociception? 888 18

Using immunohistochemistry and in situ hybridization the in vivo effects of acidic and basic fibroblast growth factor (aFGF, bFGF), and of nerve growth factor (NGF) on the expression of galanin, neuropeptide Y (NPY) and substance P in axotomized dorsal root ganglia (DRGs) were examined. Self-mutilation (autotomy), a supposed pain-related behavior, was investigated after growth factor treatment. One microgram of aFGF, bFGF or NGF was applied directly to the transected sciatic nerve via a capsule. In normal rats 3.2%, 0% and 17.5% of the neuron profiles in the DRGs contained galanin-, NPY- and substance P-like immunoreactivity (LI), respectively. Sciatic nerve transection induced a distinct increase in galanin- and NPY-LIs, but a downregulation of substance P-LI. Thus three days after axotomy 23.5%, 26.9% and 9.8% of the DRG neuron profiles showed immunoreactivity for galanin-, NPY- and substance P-LI, respectively. In vivo administration of aFGF counteracted the axotomy-induced increase in galanin and NPY, whereas bFGF only suppressed NPY upregulation. NGF reversed in the injury-induced decrease in substance P-LI, but had no significant effect on galanin- and NPY-LIs. These results were confirmed by monitoring the mRNA levels for these neuropeptides. Moreover, aFGF was found to induce autotomy in 60% of the rats 3 days after axotomy. NGF produced autotomy in about 30% of the rats. Taken together, the present results suggest (1) that aFGF, bFGF and NGF differentially regulate neuropeptide expression in vivo; (2) that FGFs can inhibit neuropeptide upregulation of some peptides after nerve injury; and (3) that aFGF and NGF may induce pain-related behavior.
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PMID:aFGF, bFGF and NGF differentially regulate neuropeptide expression in dorsal root ganglia after axotomy and induce autotomy. 891 73

ATP receptors in the central nervous system (CNS) are divided into 2 major classes, ionotropic (P2Xn) and G protein-coupled (P2Yn) ATP receptors. P2Xn receptors, a member of the 2-transmembrane family, contain non-selective cation channels that may play a role in rapid synaptic transmission. Seven subtypes of P2Xn were reported so far. Although all of these subtypes are distributed in the CNS, P2X4 and P2X6 are most abundantly and widely distributed. P2X3 is distributed only in trigeminal ganglia neurons as well as in small-diameter DRG neurons, suggesting their relation to pain. P2Yn receptors, a member of the 7-transmembrane superfamily, are coupled with Gq/11 to activate PLC beta. These receptors are thought to play an important role in the modulation of synaptic efficacy. Seven subtypes of P2Yn were reported so far. P2Y1, P2Y2, P2Y3 and P2Y4 are distributed in the CNS. Neither selective agonists nor antagonists to P2Xn and P2Yn are known.
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PMID:[ATP receptors in the central nervous system]. 939 22

Peripheral nervous system alterations were induced in adult rats by administration of cisplatin (CDDP) 2 mg/kg twice weekly for 4.5 weeks. Dorsal root ganglion neurons showed pathological changes. Morphometric determinations demonstrated a reduction in size of the somatic, nuclear and nucleolar area. The nucleoli were the most involved subcellular structures. Nerve conduction velocity and the tail-flick test for pain were both significantly altered in CDDP treated rats, whereas the rota-rod test for coordination revealed no changes in either treated or control rats. Analytical determinations demonstrated platinum accumulation in the DRG of CDDP treated rats. Spontaneous recovery, demonstrated by morphometric, electrophysiological, functional and analytical determinations, occurred after treatment discontinuation within about 7 weeks. A pilot study of the possible neuroprotective action of retinoic acid (RA) was also performed with this model of cisplatin neuronopathy. The rationale for using RA was based on its assumed antioxidant and neurotrophic effect. However, RA failed to prevent morphometric, electrophysiological, functional and analytical alterations induced by CDDP on DRG neurons. RA induced only a mild generalized protective effect.
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PMID:Experimental cisplatin neuronopathy in rats and the effect of retinoic acid administration. 952 23


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