μ-opioid Receptor-Mediated Alterations of Allergen-Induced Immune Responses of Bronchial Lymph Node Cells in a Murine Model of Stress Asthma

ABSTRACTBackgroundPsychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear.MethodsMOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured.ResultsStress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes.ConclusionsRestraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs

Tyr-Pro-Trp-Gly-NH_2(Tyr-W-MIF-1)analogであるTyr-D-Pro-Trp-Gly-NH_2の抗侵害作用におけるμオピオイド受容体の関与について

We have previously reported that Tyr-D-Pro-Trp-Gly-NH_2 (D-Pro^2-Tyr-W-MIF-1) given spinally produces clearly a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 without affecting endomorphins- and[D-Ala^2, NMePhe^4, Gly(ol)^5]-enkephalin (DAMGO)-induced antinociception, and D-Pro^2-Tyr-W-MIF-1 at any doses used (0.025-1.2 nmol) does not show any antinociception or hyperalgesic effect by itself. In the present study, we found that D-Pro^2-Tyr-W-MIF-1 given supraspinally produced the antinociception, which is mediated by stimulation of μ-opioid receptors. D-Pro^2-Tyr-W-MIF-1 (0.5-16 nmol) given intracerebroventricularly (i.c.v.) produced an apparent dose-dependent antinociception. However, at the three highest doses (4, 8 or 16 nmol), there was a ceiling effect (about 30% MPE) where the increase in dose did not lead to a greater effect. The antinociception induced by D-Pro^2-Tyr-W-MIF-1 at a dose of 4 nmol was blocked by i.c.v. co-administration with the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH_2 (CTOP), but not by i.c.v. pretreatment with the μ_1-opioid receptor antagonist naloxonazine, the κ-opioid receptor antagonist, nor-binaltorphimine, or the δ-opioid receptor antagonist naltrindole. In contrast, the antinociception induced by DAMGO and Tyr-W-MIF-1 was blocked by i.c.v. co-administration with CTOP or by i.c.v. pretreatment with higher doses of naloxonazine, but not by pretreatment with nor-binaltorphimine or naltrindole. We propose that the antinociception induced by D-Pro^2-Tyr-W-MIF-1 and Tyr-W-MIF-1 is mediated by the stimulation of different subtypes of μ_2-opioid receptors

Dermorphin tetrapeptide誘導体Tyr-D-Arg-Phe-β-AlaおよびTyr-D-Arg-Phe-β-Ala-NH_2の鎮痛作用発現におけるμ1受容体の関与

Involvement of μ1-opioid receptor on the antinociception induced by dermorphin tetrapeptide analogues Try-D-Arg-Phe-β-Ala (TAPA) and Tyr-D-Arg-Phe-β-Ala-NH_2 (TAPA-NH_2) were determined in mice, using a tail-pressure test and formalin test. TAPA and TAPA-NH_2 injected i. c. v. and i. t. produced dose-dependent antinociception in both assays. In the tail-pressure test, the antinociception induced by i. c. v. and i. t. injected TAPA, but not TAPA-NH_2, was significantly attenuated by the pretreatment with naloxonazine, selective antagonist for μ1-opioid receptor. Moreover, naloxonazine also significantly attenuated the antinociception induced by i. c. v. injected TAPA, but not TAPA-NH_2 in formalin test. In contrast, the antinociception induced by both TAPA and TAPA-NH_2 given i. t. was significantly attenuated by the pretreatment with naloxonazine in formalin test. The present results suggest that TAPA and TAPA-NH_2 should be considered to be selective agonist for μ1-and μ2-opioid receptors, respectively. The C-terminal amidation may be the critical portion for TAPA-NH_2 to distinguish μ1-and μ2-opioid receptors

セロトニン遊離薬p-chloromethamphetamineおよびfenfluramineによる雄ラットの性機能誘発効果

Methodological shortcomings present in elicitation of penile erection and ejaculation in anesthetized rats. The present study has demonstrated that intraperitoneal (i.p.) injection of p-chloromethamphetamine (PCMA ; 1-10 mg/kg) and fenfluramine (FEN ; 1-10 mg/kg), the serotonin (5-HT) releasing drugs, elicited dose-dependently both penile erection and ejaculation in anesthetized rats. PCMA (10 mg/kg) and FEN (10 mg/kg) caused an intermittent cluster of genital responses consisting of glans erections and penile cups, which closely resembles the response observed during the ex copula tests in unanesthetized rats. PCMA and FEN also caused frequent ejaculations and the weighing of ejaculates accumulated over 60 min were almost equivalent between both drugs. Pretreatment with a 5-HT synthesis inhibitor p-chlorophenylalanine (150 mg/kg × 3, i.p.) and a selective 5-HT reuptake inhibitor citalopram (1 and 3 mg/kg, i.p.) significantly inhibited the expression of both PCMA- and FEN-induced penile erection and ejaculation, while acute spinal transection (T_) did not affect the responses. These results indicate that PCMA- and FEN-induced penile erection and ejaculation in anesthetized rats are mainly elicited by the release of 5-HT which may be limited to the peripheral sites. Furthermore, the sexual responses of male rats can be easily and reliably elicited by the administration of PCMA and FEN, which may be useful for the study of the mechanisms underlying sexual functions

Dermorphin analogueであるH-Tyr-D-Arg-Phe-β-Ala-OHおよびH-Tyr-D-Arg-Phe-β-Ala-NH_2によるcapsaicinおよびsubstance P誘発性SBL行動抑制の違いについて

Intrathecal (i.t.) administration of substance P or capsaicin elicited a characteristic behavioural response consisting of scratching, biting and licking (SBL) in mice. The behavioural response induced by substance P or capsaicin was almost completely inhibited by simultaneous i. t. injection of [D-Ala^2, MePhe^4, Gly(ol)^5] enkephalin (DAMGO), H-Tyr-D-Arg-Phe-β-Ala-OH (TAPA) or H-Tyr-D-Arg-Phe-β-Ala-NH_2 (TAPA-NH_2). Pretreatment with naloxonazine significantly antagonized inhibitory action of TAPA-NH_2 on substance Pinduced SBL behavioural response without antagonistic effect against DAMGO and TAPA, while antinociceptive effect of DAMGO, TAPA and TAPA-NH_2 was completely inhibited by the pretreatment with naloxone. TAPA-induced antinociception but not DAMGO-and TAPA-NH_2-induced antinociception on behavioural response produced by i. t. capsaicin was completely inhibited by the pretreatment with naloxonazine, whereas naloxone at a dose of 1 mg/kg s. c. completely antagonized the antinociceptive effect of i. t. co-administered TAPA, DAMGO- or TAPA-NH_2. These results led us to understanding of differential action mechanism of TAPA- and TAPA-NH_2-induced antinociception, as assayed by SBL behavioural response produced by both capsaicin and substance P

冷水強制水泳誘発抗侵害作用の発現における脳内β-endorphinならびにεオピオイド受容体の関与

The involvement of endogenous opioid peptides and opioid receptors in supraspinal site on the antinociception induced by cold water swimming was determined using the mouse tail-flick test. The mice forced to swim in cold water for 3 min, showed the marked antinociception. The antinociception induced by cold water swimming was significantly attenuated by intracerebroventricularly (i.c.v.) pretreatment with antiserum against β-endorphin, but not against dynorphin A or [Leu^5] enkephalin. On the other hand, the antinociception was not affected by i.c.v. pretreatment with μ-opioid receptor antagonists β-funaltrexamine and D-Phe-cyclo-(Cys-Tyr-D-Trp-Orn-Thr-Pen)-Thr-NH_2, δ-opioid receptor antagonists naltrindole, 7-benzylidene naltrexone and naltriben, or κ-opioid receptor antagonist nor-binaltorphimine. The present results suggest that the antinociception induced by cold water swimming may be mainly mediated through the release of β-endorphin in the supraspinal site, which act on β-endorphin-sensitive non-μ-, non-δ-, and non-κ-opioid receptor, so called putative ε-opioid receptor

Endomorphin analogues containing D-Pro(2) discriminate different μ-opioid receptor mediated antinociception in mice

The antagonistic actions of D-Pro(2)-endomorphins on inhibition of the paw withdrawal response by endomorphins were studied in mice. D-Pro(2)-endomorphin-1 and D-Pro(2)-endomorphin-2, injected intrathecally (i.t.), had no significant effect on the nociceptive thermal threshold alone. When D-Pro(2)-endomorphin-1 (0.05–0.1 pmol) was injected simultaneously with i.t. endomorphin-1 (5.0 nmol) or endomorphin-2 (5.0 nmol), antinociception induced by endomoprhin-1 was reduced significantly, whereas endomorphin-2-induced antinociception was not affected by D-Pro(2)-endomorphin-1. Antinociception induced by i.t. endomorphin-2 (5.0 nmol) was reduced significantly by its analogue, D-Pro(2)-endomorphin-2 (100 pmol), but not by D-Pro(2)-endomorphin-1. D-Pro(2)-endomorphin-1. D-Pro(2)-endomorphin-1 also antagonized the antinociceptive effect of i.t. DAMGO, a μ-opioid receptor agonist, whereas D-Pro(2)-endomorphin-2 failed to reduce the effect of DAMGO. These results suggest that endomorphin analogues containing D-Pro(2) are able to discriminate the antinociceptive actions of μ(1)- and μ(2)-opioid receptor agonists at the spinal cord level

Pharmacotechnological Advances for Clinical Translation of Essential Oils for the Treatment of Pain and Agitation in Severe Dementia

The demand for natural products is steadily increasing, and pharmacotechnological engineering is needed to allow rigorous investigation of their efficacy and safety in clinical conditions representing still unmet needs. Among aged patients affected by dementia, up to 80% of residents in nursing homes suffer from chronic pain and 97% from fluctuant neuropsychiatric symptoms (NPS), of which the most challenging is agitation. It is, at least in part, due to undertreated pain and treated with antipsychotics almost doubling the risk of death. In the frame of a scoping review assessing the existence of essential oils undergoing engineering pharmacotechnological processes using solid lipid nanoparticle delivery systems for clinical translation in pain and/or neuropsychiatric symptoms of dementia following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), here we identified that the sole essential oil engineered to overcome the criticisms of aromatherapy clinical trials in pain and dementia is the essential oil of bergamot (BEO). Therefore, we present the process leading to the actually ongoing randomized, double-blind, placebo-controlled NCT04321889 clinical trial to assess the efficacy and safety of intervention with bergamot in the management of agitation and pain in severe dementia to be followed also for the proof of concept of efficacy and safety of other essential oils