Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0423716 (Neuropathic pain)
 1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
 ...
PMID:Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone. 912 15

The possible role of spinal prostanoids in the tactile allodynia and thermal hyperalgesia associated with an experimental model of neuropathic pain was investigated. Neuropathic pain was induced by tight ligation of the L5 and L6 spinal nerves. Tactile allodynia was assessed 7 days after the surgery by measuring hindpaw withdrawal threshold to probing with von Frey filaments. Thermal hyperalgesia and nociception were determined by the 52 degrees C warm-water tail-flick test and by applying radiant heat to the plantar aspect of the hindpaw ipsilateral to the ligation. Minimal antiallodynic effect was produced by intrathecal (i.th.) administration of ketorolac or morphine up to the highest testable dose (100 microg) or by the (R)- or (S)-enantiomers of ketorolac (up to 6 microg) when administered alone. However, i.th. administration of a fixed ratio (1:1) of morphine plus racemic ketorolac or of morphine plus the (S)-enantiomer of ketorolac (S-ketorolac) produced a dose- and time-related antiallodynic effect: ED50 114 +/- 35.9 microg (total dose) for morphine plus ketorolac and 70.5 +/- 21.0 microg (total dose) for morphine plus S-ketorolac. The combination of i.th. morphine plus the (R)-enantiomer of ketorolac (R-ketorolac) (up to 200 microg total dose) was without effect. Similar antiallodynic activity was obtained for the co-administration of i.th. morphine and intravenous (i.v.) racemic ketorolac. In order to investigate the role of cyclooxygenase (COX) isozymes, relatively selective COX1 (piroxicam) and COX2 N-[2-cyclohexyloxy-4-nitrophenyl] metanesulfonamide (NS-398) inhibitors were administered i.th. (60 microg) alone or together with i.th. morphine. Piroxicam, NS-398, morphine and vehicle (90% DMSO) were without significant antiallodynic effect when administered alone, but moderate antiallodynic effects were produced by i.th. administration of fixed ratio (1:1) combinations of morphine with 60 microg each (highest soluble dose) of piroxicam (%MPE = 40.8 +/- 10.2) or NS-398 (%MPE = 32.4 +/- 9.5). Further, the combined i.th. administration of morphine, piroxicam and NS-398 in fixed 1:1:1 ratio (60 microg each) resulted in a supraadditive antiallodynic effect (%MPE = 70.4 +/- 10.8). Finally, morphine, but not ketorolac, given i.th. produced dose-dependent anti nociception in either the tail-flick or the paw-flick tests. However, there was no synergy between morphine and ketorolac against thermal nociception in either of the tests. These findings suggest that spinal prostanoids produced via both COX1 and COX2 pathways may play a role in neuropathic pain states and suggest the clinical utility of opioid plus COX-inhibitor combination therapy.
 ...
PMID:Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX1- and COX2-inhibitors in nerve-injured rats. 1042 61

Mechanical allodynia- and hyperalgesia-like behavior which develops in rats after L5 spinal nerve lesion has been suggested to be due to ectopic activity in the lesioned afferent neurons originating at the lesion site and/or in the dorsal root ganglion because it is eliminated by section of the dorsal root. Here we reevaluated the effect of a dorsal rhizotomy in rats after L5 spinal nerve lesion. Using calibrated von Frey hairs, paw withdrawal threshold to single stimuli and paw withdrawal incidence to repetitive stimulation were tested before and after nerve section. Neuropathic pain behavior of similar time course and magnitude also developed after cutting the L5 dorsal root, and L5 spinal nerve lesion-induced abnormal behavior could not be reversed by dorsal rhizotomy. The neuropathic pain behavior elicited by dorsal root section also developed when impulse conduction in the dorsal root axons was blocked during rhizotomy by a local anesthetic, i.e. when the immediate injury discharge was prevented from reaching the spinal cord. These results challenge the widely accepted idea that neuropathic pain behavior developing after spinal nerve lesion is dependent on ectopic activity in the lesioned afferent neurons. However, the present results do not rule out the possibility that after the two nerve lesions the mechanisms generating neuropathic pain behavior are different. After dorsal rhizotomy neuropathic pain behavior may be related to deafferentation whereas after spinal nerve lesion it may be caused by ectopic activity.
 ...
PMID:Dorsal root section elicits signs of neuropathic pain rather than reversing them in rats with L5 spinal nerve injury. 1092 14

Increased glutamate availability in the spinal cord and primary afferent nerves plays an important role in acute and chronic pain. Afferent ectopic discharges from the site of nerve injury constitute a source of abnormal sensory input to the spinal dorsal horn. The ectopic afferent activity is largely responsible for the development of hypersensitivity of dorsal horn neurons and neuropathic pain. Inhibition of glutamate carboxypeptidase II (GCP II) reduces glutamate release generated from N-acetyl-aspartyl-glutamate in nerve tissues and may have an analgesic effect on neuropathic pain. In the present study, we determined the effect of a GCP II inhibitor, 2-(phosphono-methyl)-pentanedioic acid (2-PMPA), on allodynia and ectopic afferent discharges in an animal model of neuropathic pain. Neuropathic pain was induced by partial ligation of the left sciatic nerve in rats. Tactile allodynia was assessed using von Frey filaments applied to the plantar surface of the injured hindpaw. Single-unit activity of ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation. Intravenous injection of 50 to 100 mg/kg 2-PMPA significantly reduced allodynia in a dose-dependent manner. Furthermore, 2-PMPA dose-dependently attenuated the ectopic discharge activity of injured sciatic afferent nerves. At a dose of 100 mg/kg, 2-PMPA significantly inhibited the ectopic activity from 14.7 +/- 2.1 to 4.4 +/- 0.5 impulses/s without altering the conduction velocity of afferent nerves. Therefore, these data suggest that the antiallodynic effect of 2-PMPA may be mediated, at least in part, by inhibition of ectopic afferent discharges at the site of nerve injury.
 ...
PMID:Effect of 2-(phosphono-methyl)-pentanedioic acid on allodynia and afferent ectopic discharges in a rat model of neuropathic pain. 1180 30

Co-localization of opioid and melanocortin receptor expression, especially at the spinal cord level in the dorsal horn and in the gray matter surrounding the central canal led to the suggestion that melanocortins might play a role in nociceptive processes. In the present studies, we aimed to determine the effects of melanocortins, administered intrathecally, on allodynia, and to ascertain whether there is an interaction between opioid and melanocortin systems at the spinal cord level. Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Tactile allodynia was assessed using von Frey filaments, while thermal hyperlagesia was evaluated in cold water allodynia test. In the present experiments, melanocortin receptor antagonist, SHU9119 was much more potent than mu-opioid receptor agonist, morphine after their intrathecal (i.th.) administration in neuropathic rats. SHU9119 alleviated allodynia in a comparable manner to DAMGO, a selective and potent mu-opioid receptor agonist. Administration of melanocortin receptor agonist, melanotan-II (MTII) increased the sensitivity to tactile and cold stimulation. Moreover, we demonstrated that the selective blockade of mu-opioid receptor by cyprodime (CP) enhanced antiallodynic effect of SHU9119 as well as pronociceptive action of MTII, whereas the combined administration of mu receptor agonist (DAMGO) and SHU9119 significantly reduced the analgesic effect of those ligands. DAMGO also reversed the proallodynic effect of melanocortin receptor agonist, MTII. In conclusion, it seems that the endogenous opioidergic system acts as a functional antagonist of melanocortinergic system, and mu-opioid receptor activity appears to be involved in the modulation of melanocortin system function.
 ...
PMID:Modulation of melanocortin-induced changes in spinal nociception by mu-opioid receptor agonist and antagonist in neuropathic rats. 1249 47

The purpose of this study was to assess the possible synergistic interaction between gabapentin and B-vitamins (100:100:1 of vitamin B1, B6 and B12, respectively) in a neuropathic pain model in the rat. Neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves of female Wistar rats. Tactile allodynia was determined by measuring paw withdrawal in response to probing with a series of calibrated von Frey filaments. Gabapentin (30-300 mg/kg), B-vitamins (75-600 mg/kg), or a combination of gabapentin and B-vitamins were administered orally and the antiallodynic effect was determined. Isobolographic analyses were used to define the nature of the functional interactions between gabapentin and B-vitamins in a fixed-dose ratio (0.5:0.5). Gabapentin (ED30 23.0+/-5.3 mg/kg), B-vitamins (ED30 524.0+/-97.0 mg/kg), or a fixed-dose ratio combination of gabapentin-B vitamins combinations dose-dependently reduced tactile allodynia. The theoretical ED30 value for the combination estimated from the isobologram was 273.5+/-48.6 mg/kg. This value was significantly higher than the experimental ED30 value which was 18.7+/-1.7 mg/kg. Results indicate that systemic administration of gabapentin and B vitamins can interact synergistically to reduce neuropathic pain in the rat and suggest the use of this combination to relieve neuropathy in humans.
 ...
PMID:Oral administration of B vitamins increases the antiallodynic effect of gabapentin in the rat. 1563 18

The combination of dexamethasone and B-vitamins is widely used in Mexico to treat neuropathic pain in human beings. However, so far there is no evidence in preclinical models about the efficacy of this combination. The purpose of this study was to assess the possible synergistic interaction between dexamethasone and the B-vitamin complex in a neuropathic pain model in the rat. Neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves in female Wistar rats. Tactile allodynia was determined by measuring paw withdrawal in response to probing with a series of calibrated von Frey filaments. Dexamethasone (4-32 mg/kg), B-vitamins (75-600 mg/kg), or a combination of dexamethasone and B-vitamins (100:100:1 of vitamin B1, B6 and B12, respectively) was administered subcutaneously and the antiallodynic effect was determined. Isobolographic analyses were used to define the nature of the functional interactions between dexamethasone and B-vitamins (0.5:0.5). Dexamethasone (ED30 5.4+/-1.2 mg/kg), B-vitamins (ED30 181.1+/-2.6 mg/kg), and fixed-dose ratio dexamethasone-B-vitamins combinations dose-dependently reduced tactile allodynia in the rat. Theoretical ED30 value for the combination estimated from the isobologram was 128.2+/-5.8 mg/kg. This value was significantly higher than experimental ED30 value which was 21.8+/-2.3 mg/kg. Results indicate that subcutaneous administration of dexamethasone and B-vitamins interacted synergistically to reduce tactile allodynia in the rat and suggest the use of this combination to reduce neuropathic pain in humans.
 ...
PMID:Antinociceptive synergy between dexamethasone and the B vitamin complex in a neuropathic pain model in the rat. 1563 21

B vitamins have been used as analgesic drugs to treat pain disorders associated with their deficiency. More recently it has been claimed that B vitamins are useful to relieve different pain states as carpal tunnel, migraine and premenstrual tension. In Latin America, B vitamins are commonly used to treat neuropathic pain; however, there is no data to support this indication. In the present work we assessed the possible analgesic activity of vitamin B12 alone and combined with diclofenac in a neuropathic pain model in the rat. Neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves of female Wistar rats. Tactile allodynia was determined by measuring paw withdrawal in response to probing with a series of calibrated von Frey filaments. Vitamin B12 (0.75-6 mg/kg), but not diclofenac (1-10 mg/kg), reduced in a dose-dependent manner tactile allodynia induced by spinal nerve ligation. Diclofenac (3.2 mg/kg) was not able to further increase vitamin B12-induced antiallodynia. Results indicate that vitamin B12, but not diclofenac, produces antiallodynic effects in the rat and suggest that this vitamin could be a potential treatment for neuropathic pain in humans.
 ...
PMID:Effect of diclofenac on the antiallodynic activity of vitamin B12 in a neuropathic pain model in the rat. 1563 22

Neuropathic pain after nerve injury is severe and intractable, and current drugs and nondrug therapies offer substantial pain relief to no more than half of affected patients. The present study investigated the analgesic roles of the B vitamins thiamine (B1), pyridoxine (B6) and cyanocobalamin (B12) in rats with neuropathic pain caused by spinal ganglia compression (CCD) or loose ligation of the sciatic nerve (CCI). Thermal hyperalgesia was determined by a significantly shortened latency of foot withdrawal to radiant heat, and mechanical hyperalgesia was determined by a significantly decreased threshold of foot withdrawal to von Frey filaments stimulation of the plantar surface of hindpaw. Results showed that (1) intraperitoneal injection of B1 (5, 10, 33 and 100 mg/kg), B6 (33 and 100 mg/kg) or B12 (0.5 and 2 mg/kg) significantly reduced thermal hyperalgesia; (2) the combination of B1, B6 and B12 synergistically inhibited thermal hyperalgesia; (3) repetitive administration of vitamin B complex (containing B1/B6/B12 33/33/0.5 mg/kg, for 1 and 2 wk) produced long-term inhibition of thermal hyperalgesia; and (4) B vitamins did not affect mechanical hyperalgesia or normal pain sensation, and exhibited similar effects on CCD and CCI induced-hyperalgesia. The present studies demonstrate effects of B vitamins on pain and hyperalgesia following primary sensory neurons injury, and suggest the possible clinical utility of B vitamins in the treatment of neuropathic painful conditions following injury, inflammation, degeneration or other disorders in the nervous systems in human beings.
 ...
PMID:Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. 1592 96

Neuropathic pain is a clinical manifestation characterized by the presence of spontaneous pain, allodynia and hyperalgesia. Here, we have evaluated the involvement of CB1 cannabinoid receptors in the development and expression of neuropathic pain. For this purpose, partial ligation of the sciatic nerve was performed in CB1 cannabinoid receptor knockout mice and their wild-type littermates. The development of mechanical and thermal allodynia, and thermal hyperalgesia was evaluated by using the von Frey filaments, cold-plate and plantar tests, respectively. Pre-surgical tactile and thermal withdrawal thresholds were similar in both genotypes. In wild-type mice, sciatic nerve injury led to a neuropathic pain syndrome characterized by a marked and long-lasting reduction of the paw withdrawal thresholds to mechanical and thermal stimuli. These manifestations developed similarly in mice lacking CB1 cannabinoid receptors. We have also investigated the consequences of gabapentin administration in these animals. Gabapentin (50 mg/kg/day, i.p.) induced a similar suppression of mechanical and thermal allodynia in both wild-type and CB1 knockout mice. Mild differences between genotypes were observed concerning the effect of gabapentin in the expression of thermal hyperalgesia. Taken together, our results indicate that CB1 cannabinoid receptors are not critically implicated in the development of neuropathic pain nor in the anti-allodynic and anti-hyperalgesic effects of gabapentin in this model.
 ...
PMID:Development and expression of neuropathic pain in CB1 knockout mice. 1616 63


1 2 3 4 5 6 7 8 Next >>