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

This study evaluated the effects of spinally administered excitatory amino acid antagonists on the thermal hyperesthetic state induced by unilateral partial ligation of the sciatic nerve in the rat. The measured response was the latency to paw withdrawal of each hind paw after application of a focused heat lamp on the plantar surface of the paw through a glass plate upon which the animal stood. In this work, antagonists (MK801, DL-2-amino-5-phosphonovalerate, ketamine) of the N-methyl-D-aspartate receptor (NMDA), the glycine potentiation site at the NMDA receptor (5-chloro-indole-2-carboxylic acid) and non-NMDA receptor (kynurenic acid: g-D-glutamylaminomethyl sulphonate) were injected through chronically implanted lumbar intrathecal catheters in normal rats (no lesions) and in rats with unilateral constriction injury. In the normal rat study, NMDA and non-NMDA antagonists had little effect upon paw withdrawal latency at intrathecal doses which did not produce readily detectable motor weakness. In the hyperesthetic rat study, NMDA antagonists would temporarily eliminate the hyperesthetic state at doses below those which altered the response latency of the normal paw or which altered motor function. These results suggested that spinal NMDA receptors play an important role in the hyperesthetic state induced by peripheral nerve injury.
Pain 1992 Apr
PMID:Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. 159 73

The effects of acute administration of dizocilpine (MK-801) at different perioperative times on autotomy behavior after sciatic and saphenous nerve transection were studied in the mouse. Control mice developed a severe self-mutilating behavior starting 1-3 days postoperation and reaching a maximum by 11 days. Mice injected with a single dose of dizocilpine (0.4 mg/kg i.p.) before operation, the 1st or 3rd postoperative day autotomized significantly less than controls. An 1-wk treatment with the same dose once a day did not show further benefit. A single administration of dizocilpine the 5th day after surgery slightly halted further progression of autotomy. Dizocilpine did not have any deleterious effect on normal peripheral nerve function. These results suggest that NMDA receptor blockade prevents development of hyperalgesia and neuropathic pain after peripheral nerve injuries but only when it is administered before or during the first 3 days after injury.
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PMID:Effects of dizocilpine on autotomy behavior after nerve section in mice. 815 98

The ability of a competitive (LY274614; (+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid) and a noncompetitive (MK801; [(+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate) N-methyl-D-aspartate receptor antagonist to modulate the development of tolerance to morphine's antinociceptive (analgesic) effects was assessed by using hot-plate latency in rats. Concurrent treatment with LY274614 or MK801 by continuous s.c. infusion significantly attenuated the development of morphine tolerance produced by twice daily injections of morphine (10 mg/kg s.c.). This attenuation of morphine tolerance by LY274614 was dose-dependent, 12 or 24 mg/kg/24 hr s.c. infusion). Additionally, animals tested 1 week after the discontinuation of all drug treatments were observed to retain their analgesic sensitivity to morphine, whereas control animals remained relatively tolerant. These results suggest that LY274614 and MK801 do not alter the expression of tolerance but actually modify the development of morphine tolerance. Morphine-tolerant animals infused with LY274614 for 7 days regained their analgesic sensitivity to morphine. Furthermore, LY274614 also reversed the development of tolerance and restored morphine sensitivity in tolerant animals that continued to receive morphine. The demonstration that LY274614 can prevent and reverse the development of morphine tolerance without reducing the analgesic response suggests that the adaptive system involved in the development and maintenance of tolerance requires a functional N-methyl-D-aspartate receptor. LY274614 lacks the phencyclidine-like side effects seen with MK801, and this may favor the clinical development of this competitive N-methyl-D-aspartate receptor antagonist as an adjunct for patients receiving chronic opioids for pain management.
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PMID:Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614. 845 Apr 53

This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.
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PMID:N-methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development. 874 59

Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect +/- S.E.), at the maximum dose not yielding motor impairment, was memantine (96 +/- 5%) = AP5 (91 +/- 7%) > dextrorphan (64 +/- 11%) = dextromethorphan (65 +/- 22%) > MK801 (34 +/- 8%) > ketamine (18 +/- 6%). For the formalin test, the order of efficacy was AP5 (86 +/- 9%) > memantine (74 +/- 5%) > or = MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%) > dextromethorphan (31 +/- 12%) > ketamine (17 +/- 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.
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PMID:Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. 902 97

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (mu) and delta (delta) agonists, however, has not been reported. In these experiments, selective mu and delta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of mu agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a delta agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.
Pain 1996 Dec
PMID:Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice. 912 9

Normally-innocuous low-intensity tactile stimuli applied to inflamed tissue induce a progressive decrease in the mechanical flexion withdrawal threshold, the phenomenon of progressive tactile hypersensitivity (PTH). The effects of the mu opioid receptor agonist morphine, the non-competitive NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 on the development and maintenance of PTH has now been investigated behaviourally in rats inflamed 48 h earlier by intraplantar complete Freund's adjuvant injection. A standard protocol of eight light tactile stimuli applied to the dorsum of the inflamed paw every 4 s at 5 min intervals resulted, over 60 min, in a 70% fall in mechanical threshold from the pre-conditioning baseline value. Morphine administered before the tactile stimuli at 0.05 mg/kg i.p. had no effect on either baseline thresholds or PTH. At 0.5 mg/kg, morphine prevented the establishment of PTH without changing baseline thresholds. At 5 mg/kg morphine produced analgesia, increasing thresholds above the baseline. MK801 pre-treatment at 0.01 and 0.001 mg/kg i.p. significantly attenuated the development of progressive tactile hyperalgesia without an effect on basal thresholds. RP67580 pre-treatment at 0.1 mg/kg i.p. had no effect, but at both I and 10 mg/kg, attenuated progressive tactile hypersensitivity without changing baseline values. To test the effect of the drugs on established PTH, they were administered 90 min after the commencement of intermittent tactile stimulation to the inflamed hindpaw, when thresholds had reached a plateau. Morphine (0.5 mg/kg) and MK801 (0.01 mg/kg) produced only a small reduction in sensitivity and RP67580 (1 mg/kg) had no effect. These results suggest that the induction of inflammatory progressive tactile hypersensitivity is sensitive to morphine, and to a lesser extent NMDA and NKI receptor antagonists, but these compounds at a dose that do not alter baseline values, do not normalise established tactile hypersensitivity.
Pain 1998 Jul
PMID:Morphine, the NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inflammation-induced progressive tactile hypersensitivity. 975 18

Streptozotocin (STZ)-induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy to assess the efficacies of potential analgesic agents. We have established this model, and here we question whether the changes in nocifensive reflex activity, used as a measure of hyperalgesia, are genuinely indicative of peripheral neuropathy or may rather be attributed to the extreme poor health of the animals. For comparison we have examined animals with peripheral neuropathy induced by partial ligation of the sciatic nerve. Diabetic animals were chronically ill, with reduced growth rate, polyuria, diarrhoea, and had enlarged and distended bladders. Indicative of their poor health, diabetic animals showed markedly reduced motor activity. In contrast, following partial sciatic nerve ligation rats showed none of these adverse effects and their motor activity was not different to naive animals. Diabetic animals displayed marked mechanical hyperalgesia, and some thermal hypoalgesia. Morphine and L-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor L-NAME were without significant effect. Morphine and L-baclofen produced greater reversal of mechanical hyperalgesia following partial nerve ligation, although RP67580 and MK801 showed little or no activity. These data confirm previous findings that STZ-induced diabetes in rats produces long-lasting mechanical, but not thermal hyperalgesia. In our experience this mechanical hyperalgesia is largely resistant to a range of pharmacological tools. However, we feel that the profound ill-health of the animals, together with the poor activity of a range of potential analgesic drugs, must raise questions on the predictive value of these animals as a model for the human condition of chronic diabetic pain seen in patients receiving long-term insulin treatment, as well as ethical concerns on the use of the animals themselves.
Pain 1999 Jun
PMID:Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. 1043 18

Increased excitability of dorsal horn neurones may play a critical role in producing some pain states and there is evidence that the excitability of neurones lying throughout the dorsal horn is subject to regulation by cells in its most superficial laminae. This paper examines the effect on dorsal horn cell receptive fields and excitability of the specific activation of Lissauer's tract, a tract containing propriospinal axons which arise from cells in the substantia gelatinosa and which project to the substantia of neighbouring spinal segments. Experiments were carried out on anaesthetised spinal rats in the L3-4 spinal segments with microelectrode stimulation on the surface of the Lissauer tract (LT) and microelectrode recording of single cells or small groups of cells that responded to gentle brushing on the skin. Single shocks or brief trains of low-level stimuli to the LT produced a characteristic long-latency dorsal root potential (DRP) on the L3 dorsal root and a brief burst of firing in superficial cells with no stimulation of primary afferents. Generally, this was accompanied by no excitation of deeper dorsal horn cells but commonly by a period of inhibition, often followed by facilitation. We then turned to the effect of long periods (30-90min) of continual LT stimulation because we had seen hints of prolonged facilitation of the deeper cells after periods of such stimulation. Trains of 5 stimuli separated by 2ms and repeated every 200ms were used with individual pulses of 200 micros duration and less than 10 microA amplitude. This resulted in a shift of the effect on deep cells from primarily inhibition to mainly facilitation. We then examined in detail the effect of these long periods of LT stimulation on the size of receptive fields (RFs) of dorsal horn cells first on single units and then by repeated mapping of the RFs of small groups of cells. Control periods of 60min with no LT stimulation produced no significant RF changes but 30, 60 or 90min of LT stimulation produced successively greater expansions of RFs. When the LT stimulus was turned off after 1h, the RFs remained expanded for at least 2h. The spike height of these cells remained unchanged. The effect was not influenced by the NMDA antagonist MK801 but was imitated by the GABA(A) antagonist picrotoxin. It is concluded that the prolonged expansion of RFs could not be produced by modulation of descending control since the animals had spinal transections. Neither was it dependent on an NMDA-sensitive mechanism. With these data it is not possible to conclude whether the mechanism is pre-synaptic, post-synaptic or both. It is proposed that the most likely explanation is a decrease in the normal tonic inhibition operated in part by a GABA dependent mechanism. This phenomenon may play a role in prolonged pathological states of increased spinal cord excitability.
Pain 1999 Dec
PMID:Brief and prolonged effects of Lissauer tract stimulation on dorsal horn cells. 1056 67

NMDA-type glutamate receptors are involved in the generation and maintenance of altered pain states. In the present study, we examined the effect of an NMDA-glycine site antagonist, GV196771A [E-4, 6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H- indole-2- carboxylic acid sodium salt], on responses to noxious stimuli both in normal rats and during peripheral mononeuropathy induced by chronic constriction injury (CCI) of the sciatic nerve. In one series of experiments, activity of nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus was recorded in response to pressure stimuli to the contralateral hindpaw. Intravenous injection (iv) of the glycine antagonist had no effect on these cells in normal rats. When tested in rats with CCI induced 2-3 weeks previously, however, GV196771A (0.125, 0.5 and 2.0mg/kg) blocked responses to noxious stimulation in a dose-dependent and reversible manner. Morphine (0.5mg/kg, iv) and the NMDA channel blocker MK801 (0.1mg/kg, iv) suppressed noxious stimulus-evoked activity of VPL neurons in both normal and CCI-treated rats. MK801 also decreased the responses of non-nociceptive neurons to brush stimulation in both sets of animals, in contrast to the glycine antagonist which did not alter the responses of these cells. Similar results were obtained from a series of behavior experiments in which the latency for paw withdrawal from heat stimulation was measured in normal and CCI-treated rats. GV196771A (3 and 10mg/kg) injected orally, reduced the hyperalgesic response in the treated rats but did not change the withdrawal latency in normal rats. Taken together, these findings suggest that block of the NMDA receptor decreases nociceptive transmission in the thalamus and can modulate hyperalgesic states. GV196771A and glycine antagonists in general may represent innovative and safe agents for the treatment of neuropathic pain.
Pain 2000 Feb
PMID:Modulation of nociceptive transmission by NMDA/glycine site receptor in the ventroposterolateral nucleus of the thalamus. 1066 26


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