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Background: Limited data regarding knowledge and factors related to understanding the adverse drug reaction (ADR) reporting system of health care professionals are available in Japan. Objective: The objective of this study was to identify factors related to understanding the ADR reporting system in Miyagi Cancer Center and to find ways to increase the number and quality of ADR reports. Methods: Self-administered questionnaire surveys were administered before and after the educational meeting among health care professionals who were working in our hospital during the study period. Subanalyses restricted to nurses were also performed. Main Outcome Measure: Understanding ADR reporting system among healthcare professionals. Results: The percentage of respondents who understood the ADR reporting system in the questionnaire after the educational meeting was significantly higher than that in the questionnaire before the educational meeting. In the questionnaire after the educational meeting, multivariate logistic regression analysis found that having over 30 years of practical experience (odds ratio [OR], 3.852; 95% confidence interval [CI], 1.228-12.081 for 20-29 years, 7.695; 1.650-35.881 for over 30 years), being a physician (8.071; 1.923-33.878), being a pharmacist (18.357; 3.847-87.585), and participating in the educational meeting (5.111; 1.700-15.365) were factors associated with understanding the ADR reporting system. Multivariate logistic regression analysis of the questionnaire results before the educational meeting among nurses showed that working at outpatient departments (8.330; 3.008-23.069) was significantly and independently associated with understanding the ADR reporting system. Conclusions: The present study demonstrated that many years of practical experience, profession (physicians, pharmacists), and educational interventions were associated with good understanding of the ADR reporting system among health care professionals.

The antinociceptive effects of intrathecally (i.t.) administered high doses of spermine and spermidine, endogenous polyamines, were examined in the mouse capsaicin test. Spermine (2.5-10 nmol) and spermidine (10 and 15 nmol), when administered i.t. 5 min before the injection of capsaicin solution (1600 ng) into the plantar surface of a hindpaw, produced a significant reduction of the nociceptive behavioral response. Ifenprodil (2 and 4 nmol), an antagonist of the polyamine recognition site on N-methyl-D-aspartate (NMDA) receptor ion-channel complex, co-administered with spermine or spermidine significantly inhibited antinociception induced by both polyamines. These results indicate that spermine- and spermidine-induced antinociception may be mediated via the polyamine recognition site on NMDA receptor ion-channel complex in the mouse spinal cord.

We investigated the antinociceptive action of amlodipine, a dihydropyridine derivative, which acts on both L- and N-type voltage-dependent Ca2+ channels (VDCCs), in mice. Intrathecal injection of amlodipine (300 nmol/kg) significantly shortened the licking time in the late phase of a formalin test, while no effect was found with another dihydropyridine derivative, nicardipine (300 nmol/kg). Cilnidipine and omega-conotoxin GVIA also showed marked analgesic effects under the same experimental conditions. Transcripts of alpha1A, alpha1B, alpha1E, alpha1F, alpha1H, beta3, and beta4 subunits were detected by polymerase-chain reaction (PCR) in the dorsal root ganglion, suggesting the existence of a variety of voltage-dependent Ca2+ channels. Electrophysiological experiments showed that amlodipine and cilnidipine inhibit N-type currents in the dorsal root ganglion cells. These results suggest that amlodipine, cilnidipine, and omega-conotoxin GVIA exert their antinociceptive actions by blocking N-type Ca2+ channels in the primary nociceptive afferent fibers. Blocking of the Ca2+ channels results in attenuation of synaptic transmission of nociceptive neurons. Furthermore, it is suggested that some N-type Ca2+ channel blockers might have therapeutic potential as analgesics when applied directly into the subarachnoidal space.

We investigated the antinociceptic effects of cilnidipine, a dihydropyridine derivative which acts on both L- and N-type voltage-dependent calcium channels, in mice. Intrathecally injected cilnidipine showed significant analgesic effect in formalin test. Cilnidipine significantly suppressed N-type currents in dorsal root ganglion (DRG) cells. Our findings apparently support the idea that cilnidipine attenuates synaptic neurotransmission by inhibiting N-type calcium channels in DRG neurons.

The inhibitory effect of intracerebroventricularly-administered [D-Arg(2), beta-Ala(4)]-dermorphin (1-4) (TAPA), a highly selective mu(1)-opioid receptor agonist, on mouse gastrointestinal transit was compared with that of morphine and [D-Ala(2), N-methyl-Phe(4), Gly(5)-ol]-enkephalin (DAMGO). When administered intracerebroventricularly 5 min before the oral injection of charcoal meal, TAPA (10-100 pmol), morphine (0.25-4 nmol), and DAMGO (20-80 pmol) dose-dependently inhibited gastrointestinal transit of charcoal. The inhibitory effect of each mu-opioid receptor agonist was completely antagonized by naloxone, a nonselective opioid receptor antagonist. The inhibitory effects of morphine and DAMGO were significantly antagonized by both beta-funaltrexamine, a selective mu-opioid receptor antagonist, and naloxonazine, a selective mu(1)-opioid receptor antagonist. In contrast, the inhibitory effect of TAPA was not affected at all by beta-funaltrexamine, naloxonazine, nor-binaltorphimine (a selective kappa-opioid receptor antagonist), or naltrindole (a selective delta-opioid receptor antagonist). These results suggest that the inhibitory effect of TAPA on gastrointestinal transit may be mediated through an opioid receptor mechanism different from that of morphine and DAMGO.

Intrathecal (i.t.) administration of D-cycloserine (100 and 300 fmol), a partial agonist of the glycine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, produced a behavioral response mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank in mice, which peaked at 5 – 10 min and almost disappeared at 15 min after the injection. The behavior induced by D-cycloserine (300 fmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.5 – 2 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also dose-dependently inhibited by i.t. co-administration of 7-chlorokynurenic acid (0.25 – 4 nmol), a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex; D-(−)-2-amino-5-phosphonovaleric acid (62.5 – 500 pmol), a competitive NMDA receptor antagonist; MK-801 (62.5 – 500 pmol), an NMDA ion-channel blocker; ifenprodil (0.5 – 8 nmol); arcaine (31 – 125 pmol); and agmatine (0.1 – 10 pmol), all being antagonists of the polyamine recognition site on the NMDA receptor ion-channel complex. However, [D-Phe7,D-His9]-substance P(6 – 11), a specific antagonist for substance P (NK1) receptors, and MEN-10,376, a tachykinin NK2-receptor antagonist, had no effect on D-cycloserine-induced nociceptive behavior. These results in the mouse spinal cord suggest that D-cycloserine-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the glycine recognition site and that it does not involve the tachykinin receptor mechanism. Keywords:: D-cycloserine, N-methyl-D-aspartate (NMDA) receptor ion-channel complex, nociceptive behavior (mice), intrathecal administration

We have previously shown that spermine, a basic polyamine, and big dynorphin, a basic polypeptide, induce nociceptive behavior if injected intrathecally (i.t.) in mice (see [Pain 86 (2000) 55-61] and [Brain Res. 952 (2002) 7-14]). This suggests that other basic molecules might have the same effects. Here, i.t. administration of poly-L-lysine (12 and 36 pg) to mice was found to produce the same characteristic behavioral response, biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 0-10 min after injection. The behavior induced by poly-L-lysine (12 pg) was dose-dependently inhibited by intraperitoneal injection of morphine (0.25-4 mg/kg) and also dose-dependently, by i.t. co-administration of D-(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine hydrogen maleate (MK-801) (0.0156-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 nmol), an antagonist of the polyamine recognition site and the NR2B-containing NMDA receptor subtype. On the other hand, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe7, d-His9]-substance P (6-11), a specific antagonist for substance P (NK1) receptors, or MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit.

Intrathecal (i.t.) administration of big dynorphin (1–10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5–15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1–30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125–2 mg/kg) and also dose-dependently, by i.t. co-administration of d (−)-2-amino-5-phosphonovaleric acid (D-APV) (1–4 nmol), a competitive N -methyl- d -aspartate (NMDA) receptor antagonist, MK-801 (0.25–4 nmol), an NMDA ion-channel blocker, and ifenprodil (2–8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [ d -Phe 7 , d -His 9 ]-substance P(6–11), a specific antagonist for substance P (NK1) receptors, and MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.

We produced thiamine-deficient (TD) mice by TD diet treatment. The growth curve of mice on TD feeding was sharply increased until on the 10th day and subsequently the body weight gradually decreased. The mortality rate in mice was about 67% on the 30th day after the start of TD feeding. We performed the forced swimming test on the 10th and 20th day after the start of TD feeding. The duration of immobility in the forced swimming test was increased on the 20th day of TD feeding. Locomotor activity and motor co-ordination between the pair-fed control group and TD group on the 20th day of TD feeding were not significantly changed. Only a single injection of thiamine HCI (50 mg/kg, s.c.) on the 10th day after the start of a TD diet shortened the increased duration of immobility in the forced swimming test on the 20th day after the start of TD feeding. Whereas these reversal effects of thiamine treatment on the 20th day were not found when the treatment was given on the 19th day after the start of a TD diet. On the 20th day after the start of TD feeding, the increased duration of immobility time induced by TD was shortened by chronic administration of the tricyclic antidepressant imipramine (10 mg/kg, i.p.). These results suggested that behavioral changes in the forced swimming test might be involved in the degeneration of serotonergic and noradrenergic neurons.

Immunohistological study revealed the differential localization of subtypes of voltage-dependent calcium channels in the dorsal root ganglion neurons. Intrathecal injection of omega-conotoxin SVIB, an analogue of omega-conotoxin GVIA, which acts on N-type voltage-dependent calcium channels, significantly shortened the licking time in the late phase of a formalin test.