Search PubMed⌕ Search

Biomedical subjects

M J Field

Publications and source records attributed to M J Field.

At least 55 records · Page 3Linked to original sources
PubMed1998

Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat.

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity.

Animals↗
PubMed1997

The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret.

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, dog and ferret NK1 receptors with an approximate 300 times lower affinity for the rodent NK1 receptor. Using NK2,NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Following subcutaneous administration PD 154075 dose dependently (1-100 mg/kg) antagonised the centrally mediated [Sar9,Met(O2)11] substance P-induced foot tapping in the gerbil with a minimum effective dose (MED) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction and high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain concentration (brain/plasma ratios ranged from 0.27 to 0.41 during the time period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean +/- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently antagonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i.p.) in the ferret induces both an acute (day 1) and delayed (days 2 and 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg three times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor antagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective against the acute emetic response observed during the first 4 h following cisplatin, but it was only weakly active against the delayed response. In conclusion, PD 154075 is a selective and specific high affinity NK1 receptor antagonist with good oral bioavailability which is effective against both acute and delayed emesis induced by cisplatin in the ferret.

Animals↗
PubMed1997

Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys.

Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia.

Acetylcholine↗
PubMed1997

Human renal fibroblasts modulate proximal tubule cell growth and transport via the IGF-I axis.

To determine the paracrine interactions involved in the tubulointerstitial response to progressive renal disease, the role of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) in in vitro interactions between human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were studied in primary cell culture. PTC growth and transport were increased in the presence of CF-conditioned media (CF-CM), as shown by increased thymidine incorporation, cellular protein content and sodium-hydrogen exchange (NHE) activity, to 185 +/- 31% (P < 0.01), 150 +/- 18% (P < 0.05) and 195 +/- 27% (P < 0.01) of the control values, respectively. IGF-I was produced by cultured CF at a rate of 64.6 +/- 7.5 ng/mg protein/day. Exogenous IGF-I applied to PTC provoked similar enhancement of growth and NHE activity as CF-CM and the stimulatory effect of CF-CM was blocked by specific immunoneutralization of IGF-I receptors. These receptors were threefold more abundant on PTC basolateral versus apical membranes. IGF binding proteins (IGFBP)-2 and IGFBP-3 were secreted by CF at rates of 694 +/- 88 and 1769 +/- 45 ng/mg/day, with the release of IGFBP-3 being enhanced in the presence of PTC-CM (120.0 +/- 9.7% of control, P < 0.01). Moreover, the addition of CF-CM to PTC increased cell-associated IGFBP-3 on PTC surfaces, without changes in IGF-I receptor numbers or affinity and without changes in PTC mRNA for IGFBP-3. Des(1-3)IGF-I, an analog that binds to the IGF-I receptor but not to IGFBPs, provided a less potent stimulus for PTC growth compared with IGF-I, indicating that cell-associated IGFBP-3 facilitates the action of IGF-I on PTC. The results support important paracrine roles for both IGF-I and IGFBPs in the interstitial regulation of proximal tubule growth and transport.

Antibodies↗
PubMed1997

Gas access to the active site of Ni-Fe hydrogenases probed by X-ray crystallography and molecular dynamics.

The 2.54 A resolution structure of Ni-Fe hydrogenase has revealed the existence of hydrophobic channels connecting the molecular surface to the active site. A crystallographic analysis of xenon binding together with molecular dynamics simulations of xenon and H2 diffusion in the enzyme interior suggest that these channels serve as pathways for gas access to the active site.

Binding Sites↗
PubMed1997

Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2 delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models. 2. In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg-1) and gabapentin (10-300 mg kg-1) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg-1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg-1, s.c.). In contrast, the R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg-1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg-1. However, none of the compounds showed any effect during the early phase of the response. 3. The s.c. administration of either S-(+)-3-isobutylgaba (1-30 mg kg-1) or gabapentin (10-100 mg kg-1), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg-1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg-1, respectively. In contrast, R-(-)-3-isobutylgaba failed to show any effect in the two hyperalgesia models. 4. The intrathecal administration of gabapentin dose-dependently (1-100 micrograms/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response. 5. Unlike morphine, the repeated administration of gabapentin (100 mg kg-1 at start and culminating to 400 mg kg-1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10-300 mg kg-1), R-(-) (3-100 mg kg-1) or S-(+)-3-isobutylgaba (3-100 mg kg-1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1-100 mg kg-1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30-300 mg kg-1) and S-(+)-isobutylgaba (1-100 mg kg-1) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6. Gabapentin (30-300 mg kg-1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

Acetates↗
PubMed1997

Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro.

1. The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post-withdrawal. This ethanol-induced increase in seizure rating was unaffected by carbamazepine (30 mg kg(-1)) but significantly reduced at a higher concentration (130 mg kg(-1)). 2. Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation. 3. Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA-type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABA(A) receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA- and AMPA-type glutamate receptors. 4. Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi-component e.p.s.p. was mediated through both NMDA- and AMPA-type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice. 5. Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ-treated control neurones. 6. Prolonged ethanol ingestion is known to create a neurochemical imbalance in cortical neurones resulting in abnormal neurotransmission. The present study highlights the functional consequences that arise as a result of these neurochemical changes leading to over-excitation of neurones and pronounced epileptiform activity.

Alcoholism↗
PubMed1997

Insulin-like growth factor I stimulates apical sodium/hydrogen exchange in human proximal tubule cells.

To determine whether insulin-like growth factor I (IGF-I) stimulated apical sodium/hydrogen exchange (NHE), confluent primary human proximal tubule cells (PTC) were incubated for 48 h in serum-free media in the presence or absence of 100 ng/ml IGF-I. Cells incubated in IGF-I demonstrated significant increases in thymidine incorporation (181.2 +/- 30.3% of control values; n = 12, P = 0.01) and in resting intracellular pH (pHi) (7.52 +/- 0.08 vs. 7.30 +/- 0.06; n = 20, P < 0.05), as determined by 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein quantitative microspectrofluorometry. Following intracellular acid loading, ethylisopropylamiloride (EIPA)-inhibitable H+ efflux and 22Na+ influx after 1 min were both significantly enhanced in IGF-I-treated cells compared with controls (8.78 +/- 1.69 vs. 3.03 +/- 0.72 mM/min and 3.47 +/- 0.49 vs. 1.55 +/- 0.35 nmol x mg protein(-1) x min(-1), respectively). 22Na+ uptake studies in PTC grown on permeable supports demonstrated preferential stimulation of apical vs. basolateral NHE. The 50% inhibitory concentrations (IC50) in IGF-I-treated and control cells for EIPA (0.5 and 1.1 microM, respectively) and for HOE-694 (4.0 and 10.0 microM, respectively) were also consistent with predominant activation of apical, rather than basolateral, NHE activity. Kinetic analysis revealed an increase in maximal transport velocity (Vmax, 15.50 +/- 1.50 vs. 7.26 +/- 3.07 mM/min; n = 10, P < 0.05), without a significant change in antiporter affinity for extracellular Na+. Incubation of PTC with 100 ng/ml IGF-I produced an acute, reversible, and EIPA-inhibitable pHi increase of 0.05 +/- 0.01 pH units (n = 5, P < 0.05). The results suggest that IGF-I may contribute to the metachronous stimulation of apical NHE and PTC growth observed in many physiological and pathological conditions involving the human kidney.

Adult↗
PubMed1997

Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain.

Gabapentin and S-(+)-3-isobutylgaba are anticonvulsant agents that selectively interact with the alpha2delta subunit of voltage-dependent calcium channels. This report describes the activities of these two compounds in a rat model of postoperative pain. An incision of the plantaris muscle of a hind paw induced thermal hyperalgesia and tactile allodynia lasting at least 3 days. Postoperative testing was carried out using the plantar test for thermal hyperalgesia and von Frey hairs for tactile allodynia. A single s.c. dose of gabapentin, 1 h before surgery, dose-dependently (3-30 mg/kg) blocked the development of allodynia and hyperalgesia with a minimum effective dose (MED) of 10 and 30 mg/kg, respectively. The highest dose of gabapentin prevented development of hyperalgesia and allodynia for 24 and 49 h, respectively. Similar administration of S-(+)-3-isobutylgaba also dose-dependently (3-30 mg/kg, s.c.) prevented development of hyperalgesia and allodynia with MED of 3 and 10 mg/kg, respectively. The highest dose of S-(+)-3-isobutylgaba completely blocked development of both nociceptive responses for 3 days. The administration of S-(+)-3-isobutylgaba (30 mg/kg s.c.) 1 h after surgery also completely blocked the maintenance of hyperalgesia and allodynia, but its duration of action was much shorter (3 h). The administration of morphine (1-6 mg/kg s.c.) 0.5 h before surgery prevented the development of thermal hyperalgesia with a MED of 1 mg/kg. However, unlike gabapentin and S-(+)-3-isobutylgaba, it had little effect on the development of tactile allodynia. It is suggested that gabapentin and S-(+)-3-isobutylgaba may be effective in the treatment of postoperative pain.

Acetates↗
PubMed1996

Analysis of the low-frequency normal modes of the R state of aspartate transcarbamylase and a comparison with the T state modes.

Aspartate transcarbamylase (ATCase) is a classic example of an allosteric enzyme. It catalyzes the conversion of aspartate to carbamyl aspartate, which is the first substrate in the biosynthesis of pyrimidines. Although ATCase is well characterized, both structurally and biochemically, little is known at the atomic level about the large amplitude motions that govern its T-->R quaternary transition. We present the results of calculations of the very-low-frequency normal modes of the CTP-ligated R state ATCase, and we compare them with the equivalent modes in the CTP-ligated T state ATCase. The large-amplitude, delocalized modes of frequencies below 4 cm-1 contribute a large fraction of the atomic fluctuations observed experimentally. They show some ability to drive the R-state structure towards the T-state structure, by promoting some of the quaternary structure rearrangements that take place during the allosteric process. Their potential role in the T-->R transition is quantified and compared with the role of the low-frequency modes of the T state in the quaternary rearrangement.

Allosteric Regulation↗
PubMed1996

Modulation of the in vivo actions of morphine by the mixed CCKA/B receptor antagonist PD 142898.

The ability of a mixed CCKA/B receptor antagonist PD 142898 (benzenebutanic acid, beta-[[3-(1 H-indol-3-yl)-2-methyl-2-[[[(2-methyl- cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1 S-[1 alpha [S*(R*)]-2 beta]]) to modulate the antinociceptive, positive reinforcing and gastrointestinal actions of morphine was investigated in the rat. PD 142898 antagonised the development and maintenance of morphine (2.0 mg/kg, s.c.) induced conditioned place preference at 0.1 mg/kg, i.p. However, it potentiated the antinociceptive action of a subthreshold dose of morphine in the radiant tail flick model at doses of 0.001 and 0.01 mg/kg, s.c. Furthermore, PD 142898 (0.0001-1.0 mg/kg, s.c.) also potentiated the antinociceptive action of morphine (1.0 mg/kg, s.c.) against the late phase of formalin response associated with inflammation at the dose of 0.001-1.0 mg/kg. PD 142898 (0.001 mg/kg, s.c.) blocked the development of tolerance to morphine in the formalin test. It failed (0.001-1.0 mg/kg, i.p.) to modulate the inhibitory action of morphine (5.0 mg/kg, s.c.) on gastrointestinal transit as measured using the charcoal meal test. It is argued that the effect of PD 142898 in the conditioned place preference test involves antagonism of CCKA receptors, whilst the potentiation of the antinociceptive action of morphine is mediated via blockade of CCKB receptors. These results suggest that the mixed CCKA/B receptor antagonist may potentiate the analgesic action of morphine, block the development of tolerance without a concomitant increase in constipation and may also reduce the abuse potential of the opiate.

Animals↗
PubMed1996

Analysis of the low frequency normal modes of the T-state of aspartate transcarbamylase.

Aspartate transcarbamylase (ATCase) is an important control enzyme in the pyrimidine biosynthetic pathway in Escherichia coli. It is a classic example of an allosteric protein and has been extensively studied biochemically, kinetically and structurally. As yet, however, a detailed model for the cooperative transition between the tensed (T) and relaxed (R) forms of the protein does not exist. In this work we have calculated the low frequency normal modes of the CTP-ligated T-state of ATCase with the aim of identifying some of the motions that could be important in initiating the transition. The calculated modes, of frequencies lower than 5 per cm, produce root-mean-square coordinate deviations for the atoms which are a substantial fraction of those derived from the crystallographic B-factors. Some of the modes result in displacements which change the quaternary structure of the protein (in particular the elongation of the protein and the relative rotation of the subunits) in such a way that the R-state structure is approached. The implication of these mode motions for the overall T-->R transition process is discussed.

Allosteric Site↗
PubMed1996

Transferable circulating factors and epithelial sodium transport after unilateral nephrectomy in the rat.

1. In order to investigate the role of circulating serum factors in the altered renal haemodynamics and enhanced renal tubular transport observed in renal growth, micropuncture experiments were performed on normal animals infused with 20% plasma derived from animals in whom unilateral nephrectomy had been performed 3 days previously. 2. When animals infused with plasma from uninephrectomized animals (NxP) were compared with those infused with control plasma, the former had a higher tubular fluid flow rate measured at both the late proximal (LP; 26.7 +/- 1.6 vs. 18.4 +/- 1.4 nl min-1; P < 0.001) and early distal (ED; 14.9 +/- 1.0 vs. 7.8 +/- 1.0 nl min-1; P < 0.0001) sites, which was reflected in the final urine flow rate (16.1 +/- 3.4 vs. 5.1 +/- 0.8 microliter min-1; P < 0.005). 3. The single nephron glomerular filtration rate (SNGFR) was higher in animals infused with NxP as determined from samples taken at the LP (45.8 +/- 2.8 vs. 35.7 +/- 2.3 nl min-1; P < 0.01) and at the ED (34.5 +/- 2.5 vs. 28.1 +/- 1.8 nl min-1; P = 0.05) sites. However, this increase was not reflected in the whole kidney GFR (1.04 +/- 0.06 vs. 0.89 +/- 0.06; P = 0.07), suggestive of a preferential increase in filtration in the outer cortical nephrons. 4. Tubular Na+ transport was higher in the animals infused with NxP as evidenced by a decrease in the fractional delivery of Na+ at the ED site (4.5 +/- 0.4 vs. 6.5 +/- 0.6% of the filtered load; P < 0.05). However, in the final urine there was a significant increase in the urinary sodium excretion in animals infused with NxP (0.67 +/- 0.14 vs. 0.29 +/- 0.09%; P < 0.05) indicating that natriuresis and probably diuresis was a result of inhibition of Na+ and water transport in the late distal tubule and collecting duct. 5. In conclusion, these experiments demonstrate that circulating factors induced by a reduction in renal mass significantly alter glomerular filtration and tubular Na+ transport.

Angiotensin II↗
PubMed1996

The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine.

This report describes the activity of the antiepileptic agent gabapentin (Neurontin) in animal models predictive of anxiolysis and analgesia. Gabapentin displayed anxiolytic-like action in the rat conflict test, the mouse light/dark box and the rat elevated X-maze with respective minimum effective doses (MEDs) of 3, 10 and 30 mg/kg. Furthermore, gabapentin also induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with a MED of 30 mg/kg. In the rat formalin test of tonic nociception, gabapentin dose-dependently (30-300 mg/kg) and selectively blocked the late phase with a MED of 100 mg/kg. However, it failed to block carrageenan-induced paw oedema. The intracerebroventricular (ICV) administration of the glycine/NMDA receptor agonist D-Serine, dose-dependently (10-100 micrograms/animal) reversed the antinociceptive action of gabapentin (200 mg/kg, SC). D-Serine (30 micrograms/animal, ICV) also reversed the anxiolytic-like effects (in the light/dark box and the rat elevated X-maze) of gabapentin (30 mg/kg). In contrast, L-Serine (100 micrograms, ICV) failed to block the antinociceptive action of gabapentin. The antinociceptive action of (+)-HA-966 (25 mg/kg, SC), a partial agonist at the glycine/NMDA receptor, was reversed by D-Serine (100 micrograms/animal, ICV). However, D-Serine (100 micrograms/animal, ICV) failed to affect the antinociceptive action of a competitive NMDA receptor antagonist CGS 19755 (3 mg/kg, SC). Gabapentin has negligible affinity for the strychnine insensitive [3H]glycine binding site. This indicates that the interaction between gabapentin and D-Serine may not involve the NMDA receptor complex. Gabapentin may represent a novel type of anxiolytic and analgesic agent.

Acetates↗
PubMed1996

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine.

1. The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2. PD 140548 dose-dependently (0.001-1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0 mg kg-1, s.c.). In contrast, CI-988 (0.01-1.0 mg kg-1, i.p.) did not affect this morphine-induced behaviour. Neither of the CCK receptor antagonists blocked or generalised to the morphine (3.0 mg kg-1, i.p.) discriminative stimulus. 3. CI-988 (0.001-10.0 mg kg-1, s.c.) at doses of 0.05 and 0.1 mg kg-1 (s.c.), potentiated the antinociceptive action of a threshold dose of morphine (5.0 mg kg-1, i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg-1 it potentiated the antinociceptive action of morphine (3.0 mg kg-1) during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg-1 it also potentiated the antinociceptive action of morphine (1.0 mg kg-1) during the tonic phase of the formalin test. However, in both models, higher doses of CI-988 were ineffective. In contrast, PD 140548 (0.001-10 mg kg-1, s.c.) was only active at a dose of 1.0 mg kg-1 (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests. Chronic treatment with CI-988 (0.01 mg kg-1, s.c.) prevented the development of tolerance to morphine antinociception (4 mg kg-1, s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg-1 (i.p.). 4. Morphine dose-dependently (1-10 mg kg-1, s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01-1.0 mg kg-1, i.p.) nor CI-988 (0.01-1.0 mg kg-1, i.p.) potentiated or suppressed this inhibitory action of morphine. 5. In conclusion, the results of the present study indicate that CCKA and CCKB receptors modulate different properties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro-intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.

Analgesics, Opioid↗
PubMed1995

Peptoid CCK receptor antagonists: pharmacological evaluation of CCKA, CCKB and mixed CCKA/B receptor antagonists.

Several novel cholecystokinin (CCK) receptor ligands with differing degrees of receptor selectivity were characterised in both in vitro and in vivo models. In radioligand binding assays, the dipeptoid PD 135666 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino],-[R-(+*,S*)]) selectively inhibited [125I]Bolton Hunter CCK-8 binding to CCKB receptors in mouse cerebral cortex (CCKB IC50 = 0.1 nM) but was weaker as an inhibitor of CCKA receptor binding in the rat pancreas (IC50 = 26 nM). In contrast, its enantiomer PD 140548 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7] dec-2-yloxy)carbonyl]amino]propyl] amino],-[S-(R*,S*)) displayed the reverse selectivity (CCKA IC50 = 2.8 nM, CCKB IC50 = 260 nM). PD 142898 ([benzenebutanic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2- methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-,[1S-[1 alpha[S*(R*)],2 beta ]]) possessed nanomolar affinity for both receptor subtypes (CCKB IC50 = 4.2 nM, CCKA IC50 = 3.8 nM) whereas its corresponding enantiomer PD 142896 ([benzenebutanic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2- methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-, [1R-[1 alpha[S*(R*)],2 beta]]) displayed 147-fold selectivity for the CCKA receptor (CCKA IC50 = 7.9 nM, CCKB IC50 = 1160 nM). The pyrazolidinone PD 141479 (trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4- (trifluoromethyl)phenyl]-1-pyrazolidinecarboxamide) was found to interact selectively with the CCKB receptor (CCKB IC50 = 36 nM, CCKA IC50 = 1100 nM). PD 140548, PD 142896, PD 135666 and PD 142898 antagonised the CCKA receptor-mediated contraction of guinea pig gall bladder with respective pA2 values of 7.2, 7.4, 6.6 and 8.5. In the rat elevated X-maze, PD 135666 and PD 141479, together with the mixed CCKA/B receptor antagonist PD 142898 produced anxiolytic effects with respective minimum effective doses (MEDs) of 0.01, 0.001 and 0.01 mg/kg s.c. Furthermore, the selective CCKB receptor antagonist CI-988 (0.01-1 mg/kg) and PD 142898 (0.001-0.1 mg/kg), dose dependently induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with respective MED values of < 0.01 and < 0.001 mg/kg s.c. In contrast, compounds with the CCKA selective profile were either inactive in the two behavioural models or showed activity only at doses of 1 mg/kg and above. These data suggest that the anxiolytic effects of CCK receptor antagonists parallel their affinity for the CCKB rather than the CCKA receptor.

Animals↗