Hideki Funahashi

Hemokinin-1 mediates pruriceptive processing in the rat spinal cord

Hemokinin-1 (HK-1) is a new mammalian tachykinin peptide consisting of the amino acid sequence similar to substance P (SP). Although the function of SP, a representative tachykinin peptide, has been well established in the pain system, that of HK-1 has not yet been elucidated. [Leu(11)]-SP had an antagonistic effect on SP-induced scratching behavior, suggesting that [Leu(11)]-HK-1 may also attenuate the induction of scratching behavior by HK-1. Thus, the effects of a pretreatment with [Leu(11)]-HK-1 were evaluated to clarify the function of HK-1. The intrathecal administration of [Leu(11)]-HK-1 attenuated the induction of scratching by HK-1, but not SP, while [Leu(11)]-SP reduced the induction of scratching by SP, but not HK-1. These results indicated that [Leu(11)]-HK-1 may be a more specific antagonist of HK-1-preferred receptors and [Leu(11)]-SP has an antagonistic effect on the SP-preferred receptor, the neurokinin 1 receptor. In the formalin test for examining noxious response, the intrathecal administration of [Leu(11)]-SP, but not [Leu(11)]-HK-1, reduced the number of flinchings and c-Fos-positive cells in the spinal dorsal horn following formalin injection into the plantar region of the hind paw. These results indicated that SP, but not HK-1, is involved in nociceptive processing at the spinal level. To evaluate the involvement of HK-1 and SP in pruritic processing, the effect of [Leu(11)]-HK-1 and [Leu(11)]-SP on the induction of scratching behavior and c-Fos expression by serotonin (5-HT) and histamine was evaluated. The increased induction of scratching behavior and c-Fos expression by 5-HT and histamine was markedly attenuated by pretreatment with both [Leu(11)]-HK-1 and [Leu(11)]-SP, suggesting that HK-1 and SP may be involved in pruritic processing. These results indicate that HK-1 is involved in pruritic processing and [Leu(11)]-HK-1 is a valuable tool for clarifying the mechanisms underlying pruritic processing.

An amino-terminal fragment of hemokinin-1 has an inhibitory effect on pruritic processing in rats.

Hemokinin-1 (HK-1) is a peptide encoded by the preprotachykinin gene, TAC-4, and shares the hydrophobic carboxyl-terminal (C-terminal) region common to mammalian tachykinin peptides, such as substance P (SP). It is generally believed that C-terminal fragments of SP elicit an excitatory effect, while pretreatment with amino-terminal (N-terminal) fragments of SP inhibits the function of SP; however, there is no available information on HK-1. Therefore, to clarify the characteristics of C-terminal and N-terminal fragments of HK-1, HK-1 was divided into HK-1 (1-5) as the N-terminal fragment and HK-1 (6-11) as the C-terminal fragment based on the similarity of amino acids between HK-1 and SP. Intrathecal administration of HK-1 (6-11) induced scratching behavior similar to HK-1, while HK-1 (1-5) hardly induced scratching. Pretreatment with HK-1 (1-5), however, attenuated scratching induced by HK-1 and SP, whereas pretreatment with SP (1-5) attenuated SP-induced scratching, but not HK-1. Furthermore, intrathecal administration of HK-1 (1-5) and SP (1-5) markedly attenuated the induction of flinching and enhancement of c-Fos expression in the spinal cord following the intradermal administration of formalin, a noxious stimulant, while pretreatment with HK-1 (1-5), but not SP (1-5), markedly attenuated the induction of scratching behavior by subcutaneous administration of pruritic agents, such as serotonin or histamine. Taken together, these findings indicate that HK-1 (1-5) suppresses pruritic and nociceptive processing, while SP (1-5) suppresses nociceptive processing. Therefore, it is suggested that HK-1 (1-5) may be a useful tool for revealing pruritic processing and HK-1 may play a crucial role in pruritic processing.

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats.

OBJECTIVES We examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. METHODS Rats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. RESULTS Induction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. CONCLUSIONS These results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens.

Partial regimen replacement with aripiprazole reduces serum prolactin in patients with a long history of schizophrenia: A case series

AIM Aripiprazole (ARP) is a popular antipsychotic drug that has demonstrated ameliorative effects on hyperprolactinemia. However, no study to date has studied the utility of ARP in patients with a long history of schizophrenia and antipsychotic treatment. We therefore examined the effect of partial antipsychotic regimen replacement with ARP on hyperprolactinemia induced by chronic antipsychotic use in patients with schizophrenia. METHODS Sixteen patients with a schizophrenia diagnosis (F2) based on the International Classification of Diseases (version 10) were recruited. At months 0, 1, 3, and 6 of the study, serum prolactin, body weight, and blood glucose were measured, and QOL and psychotic symptoms were assessed using Global Assessment of Functioning scores and Clinical Global Impressions of Improvement (CGI-I) scores. RESULTS Nine patients with an average age of 46.7±9.6 years and mean disease duration of 15.9±10.4 years were included in the final analysis. Serum prolactin levels significantly decreased and GAF and CGI-I scores improved significantly over the 6-month period after partial replacement with ARP. Additionally, no changes were observed in body weight or blood glucose over the 6-month period. CONCLUSION Partial antipsychotic regimen replacement with ARP improves hyperprolactinemia, and may improve the QOL of patients with a long history of schizophrenia. CLINICAL TRIAL REGISTRATION NUMBER Japan Medical Association, Center for clinical trials D: JMA-IIA00245.

Alleviation of thalamic pain by cilostazol administration: a case report

Thalamic pain is severe and treatment‐resistant; however, there are few available options for improving thalamic pain. This study demonstrated that thalamic pain was alleviated by administration of cilostazol, suggesting that cilostazol may be a candidate for treating thalamic pain.

A survey of the effects of ramelteon on benzodiazepine-dependence: Comparison between a ramelteon add-on group and a continuous benzodiazepine administration group

In general, long-term benzodiazepine hypnotics are prescribed for patients in whom it is difficult to reduce benzodiazepine hypnotics. Unlike benzodiazepine receptor (BZ)-mediated sleep agents, ramelteon induces quasi-natural physiological sleep owing to its mechanism of action. We conducted a survey of ramelteon and BZ-dependence in patients with insomnia. Study subjects were patients with insomnia (42 cases), who were divided into a ramelteon group (22 cases; administered 8 mg/day of ramelteon before sleep in addition to BZ) and a control group (20 cases; continually administered only BZs), with a mean disease duration of 11.3 ± 9.6 years. All data were analyzed using two-way repeated measures analysis of variance. No significant difference was observed between the ramelteon group and the control group when a questionnaire concerning BZ-dependence and withdrawal symptoms was used. A significant improvement in scores at Week 16 from those at Week 0 was observed in the Pittsburgh Sleep Quality Index excerpt and in the Global Assessment of Functioning in the ramelteon group [corrected].The Wilcoxon rank-sum test showed that the number of concomitantly used BZ hypnotics decreased significantly in the ramelteon group after Week 16, while no such change was observed in the control group. Thus, by adding ramelteon to therapy for patients with long-term insomnia, we were able to reduce the number of benzodiazepine hypnotics that were used concomitantly.

Distribution of hemokinin-1 in the rat trigeminal ganglion and trigeminal sensory nuclear complex

OBJECTIVE A new mammalian tachykinin peptide encoded in a TAC4 gene was identified and designated as hemokinin-1 (HK-1). A representative of the tachykinin peptide family is substance P (SP), and the function of SP has been well characterized as a pain transmitter or modulator, while it is possible that HK-1 is involved in pruriceptive processing, but, as yet, the distribution of HK-1 peptide in the trigeminal sensory system is still unknown. Thus, the aim of the present study was to elucidate the distribution of HK-1, while comparing the expression of SP, in the trigeminal ganglion and trigeminal sensory nuclear complex. DESIGN The trigeminal ganglion and the brain stem of male SD rats were used in the immunohistochemical study. Since the amino acid sequence in the carboxyl-terminal regions of HK-1 and SP is common, polyclonal antibodies of HK-1 and SP derived from 6 amino acids consisting of amino-terminal regions of these peptides were produced in guinea pig and rabbit, respectively. The immunohistochemical staining of HK-1 and SP was conducted using frozen sections of the trigeminal ganglion and brain stem in rats. RESULTS Immunohistochemical studies revealed the expression of HK-1 in small- and medium-sized trigeminal ganglion neurons, in the paratrigeminal nucleus, and in lamina I of the trigeminal nucleus caudalis, while there was no immunoreactivity of HK-1 in the trigeminal nucleus principalis, trigeminal nucleus oralis, and trigeminal nucleus interpolaris. CONCLUSION These findings indicate that HK-1 is a target molecule for treatment of itch in the orofaicial regions.

Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease.

We previously reported that a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinsons disease showed allodynia-like withdrawal response to mechanical stimulation of the ipsilateral side of the rat hindpaw. The goal of this study was to investigate the effect of intrastriatal grafts of fetal ventral mesencephalon (VM) on the withdrawal response in 6-OHDA rats. The withdrawal threshold in response to the mechanical stimulation of the rat hindpaw was measured using von Frey filaments. In the ipsilateral side of the 6-OHDA lesions, the withdrawal threshold in response to mechanical stimulation significantly increased in 6-OHDA rats with VM grafts compared with those with sham grafts, but did not change in the contralateral side at 5 weeks after transplantation. The present results suggest that the intrastriatal grafts of fetal VM may relieve pain sensation induced by mechanical stimulation in 6-OHDA rats.

Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats.

To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin.