Biomedical subjects

Kumi Moriyama

Publications and source records attributed to Kumi Moriyama.

5 recordsLinked to original sources

PubMed2005

N-terminally truncated variant of the mouse GAIP/RGS19 lacks selectivity of full-length GAIP/RGS19 protein in regulating ORL1 receptor signaling.

The regulators of G protein signaling (RGS) are a family of proteins with conserved RGS domains and play essential roles in regulating G protein-mediated signal transduction and physiological events. GAIP/RGS19 (G alpha interacting protein, also classified as RGS19), a member of the RGS family, has been shown to negatively regulate the signaling of many G protein-coupled receptors, including the opioid receptors. Two GAIP/RGS19 mRNA variants, resulted from an alternative splicing of exon 2 of the GAIP/RGS19 gene, were identified in multiple mouse tissues. One of the transcripts consists of a complete set of exons and encodes a full-length GAIP/RGS19 protein, and the other does not have exon 2 and therefore encodes an N-terminal 22 residue truncated short GAIP/RGS19 protein. When co-expressed with either the opioid-receptor-like (ORL1) receptor or one of the mu, delta, and kappa opioid receptors, by transfecting dual-expression plasmids into COS-7 cells, the full-length GAIP/RGS19 was more effective than the N-terminally truncated variant and was more selective in regulating the ORL1 receptor signaling than in regulating the mu, delta, and kappa opioid receptors, as measured by the effectiveness to increase the agonist-stimulated GTPase activity and to reverse the agonist-induced inhibition of cyclic AMP accumulation. In the same assays, the N-terminally truncated GAIP/RGS19 did not distinguish ORL1 from the mu, delta, and kappa opioid receptors. In contrast, co-expression of RGS4 with either ORL1 or opioid receptors showed the selectivity of RGS4 for regulating opioid receptors was mu > kappa > delta > ORL1, an order completely different from that of GAIP/RGS19. The results suggest that GAIP/RGS19 prefers regulating ORL1 receptor signaling over other opioid receptors, and that the N-terminal domain of GAIP/RGS19 plays a crucial role in its receptor preference.

Alternative Splicing↗

PubMed2005

Differential expression of the regulator of G protein signaling RGS9 protein in nociceptive pathways of different age rats.

Regulators of G protein signaling (RGS) proteins are GTPase-activating proteins which act as modulators of G-protein-coupled receptors. RGS9 has two alternative splicing variants. RGS9-1 is expressed in the retina. RGS9-2 is expressed in the brain, especially abundant in the striatum. It is believed to be an essential regulatory component of dopamine and opioid signaling. In this study, we compared the expression of RGS9 proteins in the nervous system of different age groups of rats employing immunocytochemistry. In both 3-week- and 1-year-old rats, RGS9 is expressed abundantly in caudate-putamen, nucleus accumbens, and olfactory tubercle. It is also expressed abundantly in the ventral horn of the spinal cord and the dorsal root ganglion (DRG) cells. Quantitative analysis showed that the intensities of RGS9 expression in 1-year-old rats are higher than those in the 3-week-old rats in caudate-putamen, nucleus accumbens, olfactory tubercle, periaqueductal gray, and gray matter of the spinal cord. In contrast, in thalamic nuclei and locus coeruleus, the intensities of RGS9 immunostaining in 3-week-old rats are higher than in 1-year-old rats. In DRG cells, there is no significant difference between the two age groups. These data suggest that RGS9 is differentially expressed with age. Such differential expression may play an important role in neuronal differentiation and development as well as in neuronal function, such as dopamine and opioid signaling.

Afferent Pathways↗

PubMed2005

Age-dependent opioid escalation in chronic pain patients.

Rapid opioid dose escalation, possibly caused by tolerance, has been observed in some patients on daily opioid therapy, although clinically identifiable characteristics of these patients are unknown. In this retrospective chart review of 206 patients, we examined whether the age of the patient was related to opioid escalation. Initial starting doses of long-acting opioids were similar in younger patients (< or =50 yr; 49 +/- 3 mg/d oral morphine-equivalent dose) versus older patients (> or =60 yr; 42 +/- 3 mg/d). Younger patients reached a maximum dose of 452 +/- 63 mg/d over 15.0 +/- 1.3 mo, whereas older patients achieved a maximum dose of 211 +/- 23 mg/d over 14.4 +/- 1.5 mo (P < 0.0001). At the last clinic visit, younger-patient dosing averaged 365 +/- 61 mg/d, with older patients averaging 168 +/- 18 mg/d (P < 0.0001). Only older patients demonstrated a reduction in visual analog scale scores from start of opioid therapy until discharge from the clinic (6.9 +/- 0.3 to 5.6 +/- 0.3; P < 0.01). These clinical data suggest that age is an important variable in opioid dose escalation. Although factors other than opioid tolerance can result in dose escalation, it is possible that older patients may have a reduced rate of tolerance development.

Adult↗

PubMed2005

Age-dependent morphine tolerance development in the rat.

In all age groups, the use of opioids to treat chronic pain conditions has increased, yet the impact of age on opioid tolerance development has not been comprehensively addressed. In this study, we investigated age-related differences in morphine tolerance development in rats. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr were used in the study. Morphine (8 mg/kg) was injected subcutaneously twice each day and its analgesic effect assessed by the change in tail-flick latency using a thermal stimulus 5 min before and 30 min after dosing. Tolerance was defined as a 75% reduction in morphine-induced analgesia compared to Day 1. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr developed tolerance on the 4th, 10th, 14th, and 22nd days of morphine treatment, respectively. Plasma levels of morphine and its metabolites showed that pharmacokinetic differences among the groups did not correlate with the differences in tolerance development. This study demonstrates that morphine tolerance occurs more rapidly in younger rats than older rats and is unlikely to be the result of differences in drug metabolism or clearance. Aging may impact molecular processes involved in tolerance development and provide insight into novel therapeutic targets to delay opioid tolerance development.

Aging↗

PubMed2004

Role of nociceptin in the modulation of nociception in the arcuate nucleus of rats.

Neuropeptide nociceptin/orphanin FQ is the endogenous ligand for the opioid-receptor-like receptor 1 (ORL1), mediating essential functions in the central and peripheral nervous systems. The present study was performed to investigate the role of nociceptin and ORL1 receptor in nociception and morphine-induced antinociception in the arcuate nucleus of hypothalamus in rats. Hindpaw withdrawal latencies (HWL) were measured by hot-plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulation decreased significantly after intra-arcuate nucleus injection of nociceptin in a dose-dependent manner. The effect of nociceptin was blocked significantly by subsequent intra-arcuate nucleus administration of [Nphe(1)]nociceptin(1-13)-NH(2), an ORL1 receptor antagonist. Furthermore, an intra-arcuate nucleus injection of nociceptin dramatically attenuated the antinociceptive effect induced by morphine either injected in the same site or applied intraperitoneally. These results suggest that nociceptin in the arcuate nucleus induces a hyperalgesic effect by acting on ORL1 receptors. The present study also demonstrates an interaction between nociceptin and opioids in the arcuate nucleus of the hypothalamus.

Animals↗