European Journal of Pharmacology (v.387, #2)

Lethal seizures predicted after aminophylline therapy in cocaine abusers by Maciej Gasior; Jesse T Ungard; Jeffrey M Witkin (R15-R16).
Mice with a history of chronic (10 days), but not acute, treatment with a non-convulsant dose of cocaine showed increased sensitivity (P<0.001) to the toxic effects of aminophylline (seizures, lethality) relative to controls even days after the cessation of cocaine treatment. The present finding suggests that individuals with a history of cocaine use may be at increased risk for convulsive and lethal complications associated with the therapeutic use of aminophylline.
Keywords: Seizure; Lethality; Sensitization;

Differential down-regulation of the human δ-opioid receptor by SNC80 and [d-Pen2,d-Pen5]enkephalin by Takashi Okura; Scott M Cowell; Eva Varga; Thomas H Burkey; William R Roeske; Victor J Hruby; Henry I Yamamura (R11-R13).
We examined the contribution of the human δ-opioid receptor carboxyl terminal tail to (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)- and cyclic[d-Pen2,d-Pen5]enkephalin (DPDPE)-mediated receptor down-regulation. Both SNC80 and DPDPE mediated down-regulation of an epitope tagged human δ-opioid receptor. Truncation of the human δ-opioid receptor after Gly338 blocked DPDPE-mediated down-regulation. However, SNC80 mediated significant down-regulation of the truncated receptor. These findings suggest that SNC80-mediated down-regulation involves receptor domains in addition to the carboxyl terminal tail.
Keywords: δ-Opioid receptor; Down-regulation; Carboxyl terminal tail;

The effects of neuropeptide-Y were examined in the forced swim model of depression in rats. Following a 15-min preswim, four groups of rats were given three intracerebroventricular (i.c.v.) injections of neuropeptide-Y (0.5, 5, or 10 μg) or saline over a 24-h period. Several behaviors were subsequently measured during a 5-min forced swim. Neuropeptide-Y treatment dose dependently increased swimming and decreased immobility. The pattern of results is consistent with that produced by serotonergic antidepressant drugs in this model.
Keywords: Neuropeptide-Y; Stress; Depression;

Mechanism of damnacanthal-induced [Ca2+]i elevation in human dermal fibroblasts by Kazuya Aoki; Andrew Parent; John Zhang (119-124).
Damnacanthal is a potent and selective inhibitor of p56lck tyrosine kinase in a variety of tissues. We have found, however, using the Ca2+ microfluorimetry technique, that damnacanthal releases intracellular Ca2+ stores and promotes Ca2+ entry in human dermal fibroblasts. The effect of damnacanthal on the peak [Ca2+]i values and the latent time to the peak was concentration-dependent. Damnacanthal releases Ca2+ from thapsigargin-sensitive Ca2+ stores, and the Ca2+ stores responding to damnacanthal were overlapped with those of bradykinin. Damnacanthal-induced Ca2+ entry was mediated by voltage-dependent and voltage-independent Ca2+ channels. This effect of damnacanthal on intracellular Ca2+ mobilization was also observed in cultured bovine coronary endothelial cells but not demonstrated in freshly isolated rat basilar smooth muscle cells. Our study suggests that damnacanthal increases intracellular Ca2+ by releasing Ca2+ from internal stores and promoting Ca2+ entry. The relationship between the actions of damnacanthal on tyrosine kinase and intracellular Ca2+ requires further investigation.
Keywords: Tyrosine kinase; Damnacanthal; Dermal fibroblast; Ca2+, intracellular;

Mechanism of inhibition of platelet aggregation by HCL-31D by Tz-Chong Chou; Chi-Yuan Li; An-Rong Lee; Tzong-Ming Wu (125-131).
The antiplatelet effect of the pyridazinone analogue, 4,5-dihydro-6-[4-[2-hydroxy-3-(3,4 dimethoxybenzylamino)propoxy]naphth-1-yl]-3(2H)-pyridazinone (HCL-31D), was investigated in vitro with rabbit platelets. HCL-31D dose-dependently inhibited the platelet aggregation and ATP release induced by collagen (10 μg/ml), arachidonic acid (100 μM) or thrombin (0.1 U/ml) with an IC50 of about 0.95–5.41 μM. HCL-31D (0.5–5 μM) increased the platelet cyclic AMP level in a dose-dependent manner. Furthermore, HCL-31D potentiated cyclic AMP formation caused by prostaglandin E1 but not that caused by 3-isobutyl-1-methylxanthine (IBMX). HCL-31D also attenuated phosphoinositide breakdown and intracellular Ca2+ elevation induced by collagen, arachidonic acid or thrombin. HCL-31D inhibited the formation of thromboxane B2 induced by collagen or thrombin but not by arachidonic acid. In addition, HCL-31D did not affect platelet cylooxygenase and thromboxane synthase activity. These data indicate that HCL-31D is an inhibitor of phosphodiesterase and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
Keywords: HCL-31D; cAMP; Thromboxane B2; Phosphoinositide breakdown;

Characterization of the antinociceptive effects of TRK-820 in the rat by Takashi Endoh; Atsushi Tajima; Tomohiko Suzuki; Junzo Kamei; Tsutomu Suzuki; Minoru Narita; Leon Tseng; Hiroshi Nagase (133-140).
We have already reported that TRK-820, (−)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride, a new selective κ-opioid receptor agonist, has affinity for κ-subtype opioid receptors other than the κ1-opioid receptor. It would be of interest to examine whether the different κ-opioid receptor subtype properties of TRK-820 participate in its antinociceptive action in the inflamed paw test and the formalin test. TRK-820 produced a potent antinociceptive effect, which was inhibited by the selective κ-opioid receptor antagonist nor-binaltorphimine, but not by the μ-opioid receptor antagonist naloxone in the mechanical paw pressure test. TRK-820 also produced a potent antinociceptive effect in rats with adjuvant-induced arthritis. TRK-820 and morphine, a prototype μ-opioid receptor agonist, were equally effective in inhibiting the nociceptive responses in the arthritic rats and in the normal rats, while ICI-199441, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide, a κ-opioid receptor agonist, was about 5-fold less potent in the arthritic rats than in the normal rats. In the formalin test TRK-820 had a very similar antinociceptive potency to that of ICI-199441, unlike in the arthritic rats in which TRK-820 was 2.5 times more potent than ICI-199441. It is concluded that TRK-820 produced a potent antinociceptive action via the stimulation of κ-opioid receptors in rats. TRK-820 has a unique antinociceptive profile different from that of the other κ-opioid receptor agonists such as ICI-199441 in arthritic rats.
Keywords: κ-Opioid receptor agonist; Antinociceptive action; TRK-820; κ-Opioid receptor subtype;

The effects of a specific α2-adrenoceptor antagonist, atipamezole, on cognitive performance and brain neurochemistry in aged Fisher 344 rats by Antti Haapalinna; Jouni Sirviö; Ewen MacDonald; Raimo Virtanen; Esa Heinonen (141-150).
The present experiments investigated the effects of a specific and potent α2-adrenoceptor antagonist, atipamezole, on cognitive performance and neurochemistry in aged rats. Aged control Fisher 344 rats, which had lower activities of choline acetyltransferase in the frontal cortex, were impaired in the acquisition of the linear arm maze task both in terms of repetition errors and their behavioural activity (the speed of arm visits), and they needed longer time to complete this task as compared to adult control rats. Atipamezole treatment (0.3 mg/kg) facilitated the acquisition of this task in the aged rats as they committed fewer errors and completed the task more quickly than saline-treated aged control rats. A separate experiment indicated that atipamezole enhanced the turnover of noradrenaline both in the adult and aged rats, but this effect was more pronounced in the aged rats. Furthermore, atipamezole enhanced significantly the turnover of serotonin and dopamine only in the aged rats when analysed in the whole brain samples. As α2-adrenoceptor antagonists are known to alleviate akinesia in the experimental models of Parkinson's disease, the present results could be especially relevant for the development of palliative treatment for demented Parkinsonian patients.
Keywords: α2-Adrenoceptor; Atipamezole; Ageing; Memory; Cholinergic system; Noradrenergic system;

To evaluate the influence of cholinergic projections from the basal forebrain on brain metabolism, we measured the cerebral metabolic rate of glucose (CMR(glu)) after unilateral lesioning of cholinergic basal forebrain neurons with the immunotoxin 192 IgG-saporin. CMR(glu) was determined in 24 cortical and 13 sub-cortical regions using the [14C]2-deoxy-d-glucose technique of Sokoloff. Average hemispheric CMR(glu) decreased by 7% (P<0.02) and 5% (P<0.05), 7 and 21 days after lesion, respectively. Regional effects were restricted to parietal and retrosplenial cortices, lateral habenula and the basal forebrain. We have previously shown that metrifonate increased CMR(glu) in intact rats. In lesioned rats, metrifonate (80 mg/kg, i.p.) was still active but the metabolic activation was reduced in terms of both the average hemispheric CMR(glu) and the number of regions significantly affected. Although it is reduced, the sustained effect of metrifonate in lesioned rats makes an argument for the use of this compound as treatment of cholinergic deficit in Alzheimer's disease.
Keywords: Cholinergic system; Cholinesterase inhibitor; Cerebral metabolism; Alzheimer's disease; Nucleus basalis;

Enhanced δ-opioid receptor-mediated antinociception in μ-opioid receptor-deficient mice by Chunyuan Qiu; Ichiro Sora; Ke Ren; George Uhl; Ronald Dubner (163-169).
Inflammatory hyperalgesia was induced in wild-type, heterozygous and μ-opioid receptor knockout mice after an intraplantar injection of complete Freund's adjuvant. μ-Opioid receptor knockout mice exhibited faster recovery from hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice. Naloxone restored hyperalgesia in all genotypes. Naltrindole (δ-opioid receptor-selective antagonist) partially restored the hyperalgesia only in μ-opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (κ-opioid receptor-selective antagonist) had no effect. The μ-opioid receptor-selective agonist, [d-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in μ-opioid receptor knockout mice while U69,593 {(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide, κ-opioid receptor-selective} produced similar effects in all mice. The δ-opioid receptor-selective agonists, [d-Pen2, d-Pen5]enkephalin (DPDPE) and deltorphin ([d-Ala2]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P<0.05). The findings suggest that μ-opioid receptors may be involved in the persistence of inflammatory hyperalgesia and that a δ-opioid receptor-mediated compensatory mechanism in the absence of the μ-opioid receptor is activated by persistent hyperalgesia.
Keywords: Inflammation; μ-Opioid receptor; Knockout mice;

Differential effects of nicotine against stress-induced changes in dopaminergic system in rat striatum and hippocampus by Robert Pawlak; Yumiko Takada; Hiroshi Takahashi; Tetsumei Urano; Hayato Ihara; Nobuo Nagai; Akikazu Takada (171-177).
A number of studies have shown an increase in nicotine self-administration among smokers when exposed to stress. Since it is well known that nicotine or stress alter the dopaminergic system, we examined the effect of chronic nicotine administration on the dopamine level and its metabolism in the striatum and the hippocampus during stressful conditions in rats. Nicotine (0.4 mg/kg, i.p. for 14 days) increased the dopamine level in the striatum (P<0.05) and decreased it in the hippocampus (P<0.05) in comparison with the effect of saline. Three hours of water-immersion restraint stress sharply elevated the dopamine level (P<0.05) and reduced the 3-methoxytyramine level (P ranged from 0.05 to 0.001 depending on the area and time point) in both brain regions studied, while dihydroxyphenylacetic acid and homovanilic acid levels were not altered. Nicotine pretreatment attenuated some of these changes in a region- and time-dependent manner. However, stress induced a decrease in dopamine turnover in the hippocampus (P<0.05) but not in the striatum, and nicotine failed to prevent this effect. Stress-induced alterations gradually returned toward normal during the 48-h observation period, and in some cases this was facilitated by nicotine. Thus, we demonstrated differential, region- and time-dependent protective effects of chronic nicotine administration against stress-induced changes in dopamine levels and release in brain regions critically affected by stress.
Keywords: Stress; Nicotine; Dopamine; Striatum; Hippocampus; (Rat);

Imaging extrastriatal dopamine D2 receptor occupancy by endogenous dopamine in healthy humans by Masahiro Fujita; N.Paul L.G. Verhoeff; Andrea Varrone; Sami S. Zoghbi; Ronald M. Baldwin; Peter A. Jatlow; George M. Anderson; John P. Seibyl; Robert B. Innis (179-188).
The effect of endogenous dopamine on in vivo measurement of dopamine D2 receptors in extrastriatal regions (thalamus and temporal cortex) was evaluated with single photon emission computed tomography and the high affinity ligand [123I]epidepride by comparing the binding potential before and after acute dopamine depletion. Dopamine depletion was achieved by per-oral administration of 5.5 g/70 kg body weight α-methyl-para-tyrosine given in 37 h. The α-methyl-para-tyrosine treatment increased the binding potential significantly in the temporal cortex (13±15%, P=0.036) but not in the thalamus (2±9%). The increase of the binding potential in the temporal cortex correlated strongly with the increase of dysphoric mood evaluated by the Positive and Negative Symptom Scale (PANSS) (ρ=0.88, P=0.004). These results imply that [123I]epidepride, coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration.
Keywords: Dopamine; Dopamine D2 receptor; [123I]Epidepride; SPECT (Single photon emission computed tomography); α-Methyl-para-tyrosine; Schizophrenia; Binding, in vivo;

Opposite modulation of apomorphine- or amphetamine-induced stereotypy by antagonists of CCK receptors by Carla A Tieppo; Flávio S Ferreira; Alexandre S Sassatani; Luciano F Felicio; Antonia G Nasello (189-196).
Stereotyped behavior is elicited by activation of dopaminergic systems with drugs such as apomorphine and amphetamine. In previous studies, we have reported that the sulfated cholecystokinin octapeptide (CCK-8) decreased apomorphine-induced stereotypy in animals with normal and supersensitive dopamine receptors. The aim of the present study was to evaluate the effects of CCK1 and CCK2 receptor antagonists on stereotyped behavior induced by apomorphine or amphetamine. Rats were pretreated with the CCK1 (SR 27897B; 1-[[2-(4-(2-chlorophenyl) thiazol-2-yl) aminocarbonyl]indolyl]acetic acid; 500 μg/kg; i.p.) or CCK2 (L-365,260; 3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5 phenyl-1H-1,4-benzodiazepine-3-yl)-N′-(3-methyl phenyl)-urea; 500 μg/kg; i.p.) receptor antagonists or saline 15 min before apomorphine (0.6 mg/kg; s.c.) or amphetamine (9.0 mg/kg; i.p.) injection. Both CCK1 and CCK2 receptor antagonists significantly increased apomorphine-induced stereotypy. In contrast, only the blockade of CCK2 receptors significantly decreased amphetamine-induced stereotypy. The results suggest a dual opposite mechanism for CCK–dopamine interactions. These data also suggest that both apomorphine- and amphetamine-induced stereotypy should be used whenever effects of drugs acting on dopaminergic systems are being assessed.
Keywords: SR 27897B; L-365,260; Cholecystokinin; Dopamine; CCKA receptor; CCKB receptor;

Effects of RO 60 0175, a 5-HT2C receptor agonist, in three animal models of anxiety by Guy Kennett; Sean Lightowler; Brenda Trail; Fiona Bright; Steven Bromidge (197-204).
There is some controversy as to whether 5-HT2C receptor agonists are anxiogenic or anxiolytic. The effects of the novel 5-HT2C receptor agonist, (S)-2-chloro-5-fluoro-indol-1-yl)-1-methyl ethylamine fumarate (RO 60 0175), in three models of anxiety were therefore tested. RO 60 0175 was found to induce hypolocomotion in rats at doses greater than 0.5 mg/kg s.c., an effect reversed by the selective 5-HT2C receptor antagonist, SB-242084. RO 60 0175 did not elicit anxiolytic-like responses in the social interaction test under high light unfamiliar conditions, but suppressed both time spent in social interaction and locomotion at doses of 1 and 3 mg/kg s.c., suggesting a sedative response. In the Vogel conflict test, RO 60 0175 had no significant action on the number of shocks taken. In the Geller–Seifter test, RO 60 0175 (0.3 and 1 mg/kg s.c.) simultaneously reduced both unpunished and punished lever pressing, a profile consistent with sedation. Finally, RO 60 0175 was tested in a rat social interaction test under low light familiar conditions optimal for the detection of anxiogenic-like responses. At 1 and 3 mg/kg s.c., RO 60 0175 reduced both time spent in social interaction and concurrent locomotion, a profile more consistent with sedation than anxiogenesis. In conclusion, RO 60 0175 induced sedative-like responses via 5-HT2C receptor activation, but was neither anxiolytic, nor clearly anxiogenic at the doses tested.
Keywords: Anxiety; Depression; 5-HT2C receptor; (Rat);

The effects of valproate on the arachidonic acid metabolism of rat brain microvessels and of platelets by Zoltán Szupera; Zsófia Mezei; Béla Kis; Árpád Gecse; László Vécsei; Gyula Telegdy (205-210).
Long-term administration of the antiepileptic drug valproate can induce hematologic, hepatic and endocrine abnormalities and morphologic alterations in the brain capillaries and glial cells. Valproate elicits bone marrow suppression, reducing the number of red blood cells and platelets, and causes platelet functional abnormalities. Various data suggest that more than one mechanism of valproate-associated toxicity may exist, but the pathomechanism of cell function alterations elicited by valproate has not yet been elucidated. The reported ex vivo experiments were designed to investigate the effects of valproate on the arachidonic acid cascade of rat brain capillaries and platelets. Valproate was administered (300 mg/kg body weight/day) in the drinking water to male Wistar rats for 2 weeks. Isolated platelets and brain microvessels were labelled with [14C]arachidonic acid and the released [14C]eicosanoids were separated by overpressure thin-layer chromatography and determined quantitatively by liquid scintillation counting. Valproate treatment reduced the synthesis of cyclooxygenase and lipoxygenase products in rat platelets. In brain microvessels valproate stimulated the synthesis of lipoxygenase metabolites and attenuated the cyclooxygenase pathway. Modifications of the arachidonate cascade in platelets and brain microvessels may contribute to the cell function alterations caused by valproate.
Keywords: Valproate; Arachidonic acid cascade; Platelet; Brain microvessel;

Effects of inhibitors for tyrosine kinase and non-selective cation channel on capacitative Ca2+ entry in rat ileal smooth muscle by Toshio Ohta; Wakana Yasuda; Akiyo Hasegawa; Shigeo Ito; Yoshikazu Nakazato (211-220).
The effects of tyrosine kinase inhibitors and non-selective cation channel blockers on capacitative Ca2+ entry were examined in the presence of methoxyverapamil in rat ileal smooth muscles. In Ca2+-free solution, carbachol or caffeine produced a rapid contraction mediated by Ca2+ release from the stores (Ca2+-release response), and then led to Ca2+ depletion of the stores. Subsequently, reintroduction of Ca2+ caused a transient contraction due to capacitative Ca2+ entry. Tyrosine kinase inhibitors, genistein and tyrphostin 47 but not herbimycin A, suppressed the responses to Ca2+-reintroduction much greater than Ca2+-release responses to carbachol or caffeine. Similar inhibitory effects on the responses to Ca2+-reintroduction were obtained with daidzein and tyrphostin A1, respective inactive analogue of genistein and tyrphostins. After continuous depletion of the stores with thapsigargin, Ca2+-reintroduction produced a sustained contraction, which was inhibited by these agents to different extents, but not by herbimycin A. In β-escin-treated skinned muscles, genistein slightly reduced Ca2+-induced contraction. In fura-2-loaded tissues, SK&F 96365 inhibited contractile and [Ca2+]i responses to Ca2+-reintroduction but minimally affected Ca2+-release responses. Tetrandrine suppressed both responses to Ca2+-reintroduction and to Ca2+-release. These results suggest that genistein and tyrphostin 47 inhibit capacitative Ca2+ entry through an inhibition of Ca2+ entry channels rather than tyrosine kinase. SK&F 96365, but not tetrandrine, seems to selectively inhibit the contractile responses to capacitative Ca2+ entry in rat ileal smooth muscles.
Keywords: Ca2+ entry; Ca2+ store; Fura-2; Cation channel; Tyrosine kinase;

Choleretic activity of phloracetophenone in rats: structure–function studies using acetophenone analogues by Pawinee Piyachaturawat; Nitjagan Chai-ngam; Aporn Chuncharunee; Prayad Komaratat; Apichart Suksamrarn (221-227).
The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8±6.1 μl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials.
Keywords: Acetophenone analogue; Choleretic; Cholesterol; (Curcuma comosa); Lithogenic index; Phloacetophenone;

Fas ligand, which is a type II membrane protein, is a major inducer of apoptosis. The effect of glycyrrhizin on anti-Fas antibody-induced hepatitis in mice was studied. Pretreatment of mice with glycyrrhizin (100, 200 and 400 mg/kg, i.p.) inhibited the anti-Fas antibody (150 μg/kg, i.v.)-induced elevation of plasma aminotransferase activity in a dose-dependent manner. CPP32 is a cystein protease and CPP32-like activity induced by anti-Fas antibody injection was inhibited by glycyrrhizin (200 mg/kg). However, the addition of glycyrrhizin (up to 10−4 M) to a liver cytosol fraction isolated from mice treated with anti-Fas antibodies (150 μg/kg, i.v.) did not inhibit the CPP32-like activity in vitro. The present results clearly show that glycyrrhizin inhibited anti-Fas antibody-induced hepatitis by acting upstream of CPP32-like protease activation.
Keywords: Fas; Glycyrrhizin; Hepatitis;

Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrol-2-acetamido acetate) (MED15) is a new nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties similar to the traditional drugs, but with unexpected gastroprotective effects. In an in vivo rat model, amtolmetin guacyl administered orally demonstrates inhibition of gastric acid secretion following stimulation by various agonists, and up-regulation of gastric bicarbonate production. Pretreatment with MED15 also shows a significant reduction of indomethacin-induced gastric damage in the rat. The reason behind this behaviour appears to be bound to the presence in the MED15 molecule of a vanillic moiety known to stimulate capsaicin receptors. In fact, the antisecretive effect of MED15 is blocked by capsazepine (a specific capsaicin receptor antagonist). This effect is confirmed by the interference found with anti-histamine H1 drugs. Owing to the connection between capsaicin and calcitonin gene-related peptide (CGRP), a possible effect of MED15 on CGRP receptors was hypothesized, considering the leading role played on gastric mucosa by the predominant sensory neuropeptide of the stomach wall, CGRP. In fact, the anti-secretive and gastroprotective effect of MED15 is abolished by CGRP-(8–37) (the specific CGRP receptor antagonist). The unmodified MED15 molecule is found throughout the gastroenteric tract for long periods of time following oral administration, as further confirmation of the mechanism of action being based on the presence of the vanillic moiety at receptor level.
Keywords: Amtolmetin guacyl; Antisecretion; Gastroprotection; Capsaicin; CGRP (calcitonin gene-related peptide);