Yuriko Iwamoto

Streptozotocin-induced diabetes selectively reduces antinociception mediated by μ1-opioid receptors, but not that mediated by μ2-opioid receptors

We assessed the effect of naloxonazine, a selective mu 1-opioid receptor antagonist, on antinociception produced by intrathecal or intracerebroventricular injections of morphine in streptozotocin-induced diabetic mice. The antinociceptive effect of morphine (10 micrograms), administered i.c.v., was significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effect of i.c.v. morphine was significantly reduced in both diabetic and non-diabetic mice following pretreatment with naloxonazine. There were no significant differences in the antinociceptive effect of morphine (1 microgram, i.t.) in diabetic and non-diabetic mice. Furthermore, naloxonazine had no significant effect on the antinociceptive effect of i.t. morphine in either diabetic or non-diabetic mice. On the other hand, the antinociceptive effects of i.c.v. and i.t. morphine were significantly reduced following pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist, in both diabetic and non-diabetic mice. In conclusion, mice with diabetes are selectively hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception, but are normally responsive to activation of spinal mu 2-opioid receptors.

Antitussive effects of naltrindole, a selective δ-opioid receptor antagonist, in mice and rats

Abstract The effects of naltrindole, a selective δ-opioid receptor antagonist, on the capsaicin-induced cough reflex in mice and rats were studied. Intraperitoneal administration of naltrindole decreased the number of coughs both in mice and rats dose dependently. The cough-depressant effects reached a peak 15 min after the administration of naltrindole and lasted more than 120 min. Pretreatment with [ D -Pen 2 , D -Pen 5 ]enkephalin, a selective δ-opioid receptor agonist, partially but significantly reduced the antitussive effect of naltrindole. Blockade of ϰ-opioid receptors by pretreatment with nor-binaltorphimine also partially antagonized the antitussive effect of naltrindole. However, the antitussive effect of naltrindole was not antagonized by β-funaltrexamine, a selective μ-opioid receptor antagonist. Thus, it is possible that the antitussive effect of naltrindole may be mediated, in part, by ϰ-opioid receptors. The present results provide evidence for the development of δ-opioid antagonists, especially naltrindole, for use as antitussive drugs.

Effects of diabetes on spontaneous locomotor activity in mice

Spontaneous locomotor activity in diabetic mice was significantly greater than that in non-diabetic mice. Haloperidol and SCH23390, a selective dopamine D1-receptor antagonist, significantly reduced spontaneous locomotor activity in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity in diabetic mice was also reduced by pretreatment with naltrindole, a selective delta-opioid receptor antagonist, and 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist. The rate of dopamine turnover in the limbic forebrain in diabetic mice was significantly higher than that in non-diabetic mice. These findings suggest that the enhanced spontaneous locomotor activity in diabetic mice may result from increased dopamine neurotransmission, which might be due to an increase in dopamine release in mesolimbic dopamine systems. The increased dopamine neurotransmission in diabetic mice may also be due to the up-regulation of delta-opioid receptor-mediated functions.

Streptozotocin-induced diabetes selectively enhances antinociception mediated by δ1-but not δ2-opioid receptors

Abstract We assessed the effect of diabetes on antinociception produced by intracerebroventricular injection of δ-opioid receptor agonists [D-Pen 2,5 ]enkephalin (DPDPE) and [D-Ala 2 ]deltorphin II. The antinociceptive effect of DPDPE (10 nmol), administered i.c.v., was significantly greater in diabetic mice than in non-diabetic mice. The antinociceptive effect of i.c.v. DPDPE was significantly reduced in both diabetic and non-diabetic mice following pretreatment with 7-benzylidenenaltrexone (BNTX), a selective δ 1 -opioid receptor antagonist, but not with naltriben (NTB), a selective δ 2 - opioid receptor antagonist. There were no significant differences in the anticiceptive effect of [D-Ala 2 ]deltorphin II (3 nmol, i.c.v.) in diabetic and non-diabetic mice. Furthermore, the antinociceptive effect of i.c.v. [D-Ala 2 ]deltorphin II was significantly reduced in both diabetic and non-diabetic mice following pretreatment with NTB, but not with BNTX. In conclusion, mice with diabetes are selectively hyper-responsive to supraspinal δ 1 -opioid receptor-mediated antinociception, but are normally responsive to activation of δ 2 -opiod receptors.

Antinociceptive effect of L-arginine in diabetic mice.

The antinociceptive effect of L-arginine in streptozotocin-induced diabetic mice was examined. Although s.c. administration of L-arginine produced a dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The antinociceptive effects of L-arginine in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective delta-opioid receptor antagonist. However, neither beta-funaltrexamine, a selective mu-opioid receptor antagonist, nor nor-binaltorphimin ++, a selective kappa-opioid receptor antagonist, significantly affected the antinociceptive effect of L-arginine in diabetic and non-diabetic mice. These results suggest that L-arginine produces a marked antinociceptive effect in diabetic mice through the activation of delta-opioid receptors.

Involvement of δ1-opioid receptor antagonism in the antitussive effect of δ-opioid receptor antagonists

Abstract The effects of 7-benzylidenenaltrexone(BNTX), a selective δ 1 -opioid receptor antagonist, and naltriben, a selective δ 2 -opioid receptor antagonist, on the capsaicin-induced cough reflex were studied in mice. I.p. administration of BNTX in doses from 0.1 to 3.0 mg/kg reduced the number of coughs dose dependently. The antitussive effect of BNTX was antagonized by [ D -Pen 2,5 ]enkephalin (DPDPE), a selective δ 1 -opioid receptor agonist, while [ D -Ala 2 ]deltorphin II, a selective δ 2 -opioid receptor agonist, had no effect on the antitussive effect of BNTX. Pretreatment with nor-binoltorphimine, a selective κ-opioid receptor antagonist, had no significant effect on the antitussive effect of BNTX. I.p. administration of naltriben, in doses of 1 and 3 mg/kg, also significantly decreased the number of coughs. Although the antitussive effect of naltriben was antagonized by nor-binaltorphimine, the antitussive effect of naltriben was not attenuated by either DPDPE or [ D -Ala 2 ]deltorphin II. The antitussive effects of neither BNTX nor naltriben were antagonized by β-funaltrexamine, a selective μ-opioid receptor antagonist. Thus, it seems likelythat the δ 1 -opioid receptor antagonism may be involved in the antitussive effect of δ-opioid receptor antagonists.

Possible involvement of μ2-mediated mechanisms in μ-mediated antitussive activity in the mouse

Abstract The effect of pretreatment with naloxonazine on μ-opioid agonist-mediated antitussive effects was studied in mice. The antitussive effects of [ d -Ala 2 , MePhe 4 , Gly-ol 5 ]enkephalin (DAMGO) and morphine were significantly antagonized by naloxone pretreatment, 1 mg/kg given i.p. 5 min earlier, but not by naloxonazine pretreatment, 35 mg/kg given s.c. 24 h earlier. In contrast, the antinociceptive effects of these μ agonists, as determined by the tail-flick method, were significantly reduced by pretreatment with both naloxone and naloxonazine. These results suggests that μ 2 rather than μ 1 mechanisms are involved in μ-mediated antitussive effects.

The role of the μ2-opioid receptor in the antitussive effect of morphine in μ1-opioid receptor-deficient CXBK mice

The effect of morphine on the capsaicin-induced cough reflex was studied in mu 1-opioid receptor-deficient CXBK mice. There was no significant difference between the morphine-induced antitussive effect in CXBK mice and C57BL/6 mice, a progenitor strain. Furthermore, the antitussive effects of morphine in both the CXBK and C57BL/6 mice were antagonized by pretreatment with either naloxone or beta-funaltrexamine, a mu-opioid receptor antagonist, whereas pretreatment with naltrexonazine, a selective mu 1-opioid receptor antagonist, had no effect. Moreover, naltrindole, a selective delta-receptor antagonist, also had no significant effect on the antitussive effects of morphine in either CXBK or C57BL/6 mice. These results support our previous hypothesis that mu 2- rather than mu 1-opioid receptors are involved in morphine-induced antitussive effects.

Differential modulation of μ-opioid receptor-mediated antitussive activity by δ-opioid receptor agonists in mice

Abstract We examined the effect of [D-Ala2]deltorphin II, a selective δ2-opioid receptor agonist, on the antitussive effect of [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO), a selective μ-opioid receptor agonist. [D-Ala2]deltorphin (3 nmol i.c.v.) had no significant effect on the number of coughs. However, upon i.c.v. pretreatment with [D-Ala2]deltorphin II (3 nmol) the antitussive activity of DAMGO (0.03 nmol) was significantly enhanced. The enhancement of the antitussive activity of DAMGO caused by [D-Ala2]deltorphin II was prevented by a benzofuran derivative of naltrindole (0.1 mg/kg s.c.), a selective δ2-opioid receptor antagonist. These results suggest that δ2-opioid receptors may play a synergistic role in antitussive processes that are mediated by μ-opioid receptors.

Involvement of haloperidol-sensitive σ-sites in antitussive effects

Abstract The effects of selective σ-ligands on the capsaicin-induced cough reflex in rats were studied. Intraperitoneal injection of (+)-N-allylnormetazocine ((+)-SKF-10,047) and N,N′-di(ortho-toly)guanidine (DGT) in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs dose dependently. The antitussive effects of these σ-ligands were significantly attenuated by pretreatment with haloperidol. Pretreatment with haloperidol also markedly reduced the antitussive effects of (±)-pentazocinc and dextromethorphan. These results suggest that haloperidol-sensitive σ-sites may be involved in the regulation of coughs.