In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)‐AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited ...by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)‐AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5–L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2‐mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up‐regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)‐AM1241 dose dependently (EC50 of 3.6 and 4.5 nm, respectively) reduced capsaicin‐induced calcitonin gene‐related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)‐AM1241 and L768242, respectively) of the dose–response curve. Experiments on capsaicin‐induced CGRP release in tissue from CB1–/– mice ruled out a CB1‐mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non‐neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.
The effect of “prophylactic” environmental stimulation on clinical symptoms and presynaptic defects in mice suffering from the experimental autoimmune encephalomyelitis (EAE) at the acute stage of ...disease (21 ± 1 days post immunization, d.p.i.) was investigated. In EAE mice raised in an enriched environment (EE), the clinical score was reduced when compared to EAE mice raised in standard environment (SE).Concomitantly, gain of weight and increased spontaneous motor activity and curiosity were observed, suggesting increased well-being in mice. Impaired glutamate exocytosis and cyclic adenosine monophosphate (cAMP) production in cortical terminals of SE-EAE mice were evident at 21 ± 1 d.p.i.. Differently, the 12 mM KCl-evoked glutamate exocytosis from cortical synaptosomes of EE-EAE mice was comparable to that observed in SE and EE-control mice, but significantly higher than that in SE-EAE mice. Similarly, the 12 mM KCl-evoked cAMP production in EE-EAE mice cortical synaptosomes recovered to the level observed in SE and EE-control mice. MUNC-18 and SNAP25 contents, but not Syntaxin-1a and Synaptotagmin 1 levels, were increased in cortical synaptosomes from EE-EAE mice when compared to SE-EAE mice. Circulating IL-1β was increased in the spinal cord, but not in the cortex, of SE-EAE mice, and it did not recover in EE-EAE mice. Inflammatory infiltrates were reduced in the cortex but not in the spinal cord of EE-EAE mice. Demyelination was observed in the spinal cord; EE significantly diminished it. We conclude that “prophylactic” EE is beneficial to synaptic derangements and preserves glutamate transmission in the cortex of EAE mice.
This article is part of the Special Issue entitled “Neurobiology of Environmental Enrichment”.
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•Enriched environment (EE) ameliorates clinical score and behaviours in EAE mice.•Inflammatory infiltrates and spinal demyelination are reduced in EE-EAE mice.•EE preserves glutamate exocytosis efficiency from cortical terminals.•cAMP production from cortical synaptosomes is unaltered in trained EAE mice.•EE increases the expression of MUNC-18 and SNAP-25 in the cortex.
BACKGROUND AND PURPOSE
URB937 is a peripherally restricted inhibitor of the anandamide‐deactivating enzyme fatty‐acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces ...marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP‐binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoplacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats.
EXPERIMENTAL APPROACH
We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid‐induced writhing) and inflammatory nociception (carrageenan‐induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the blood‐placenta barrier in gestating mice and rats.
KEY RESULTS
Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to placental and fetal tissues in pregnant mice and rats.
CONCLUSIONS AND IMPLICATIONS
Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoplacental unit.
LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue‐8
In the biomedical sector the availability of engineered scaffolds and dressings that control and reduce inflammatory states is highly desired, particularly for the management of burn wounds. In this ...work, we demonstrate for the first time, to the best of our knowledge, that electrospun fibrous dressings of poly(octyl cyanoacrylate) (POCA) combined with polypropylene fumarate (PPF) possess anti-inflammatory activity and promote the fast and effective healing of mild skin burns in an animal model. The fibers produced had an average diameter of (0.8 ± 0.1) µm and they were able to provide a conformal coverage of the injured tissue. The application of the fibrous mats on the burned tissue effectively reduced around 80% of the levels of pro-inflammatory cytokines in the first 48 h in comparison with un-treated animals, and enhanced skin epithelialization. From histological analysis, the skin thickness of the animals treated with POCA : PPF dressings appeared similar to that of one of the naïve animals: (13.7 ± 1.4) µm and (14.3 ± 2.5) µm for naïve and treated animals, respectively. The density of dermal cells was comparable as well: (1100 ± 112) cells mm(-2) and (1358 ± 255) cells mm(-2) for naïve and treated mice, respectively. The results demonstrate the suitability of the electrospun dressings in accelerating and effectively promoting the burn healing process.
Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor, regulates several central functions such as pain transmission, learning and memory, fear and anxiety and feeding and ...locomotor activity. It has been recently reported that NOP receptor antagonists induce antidepressant‐like effects in the mouse forced swimming test (FST), i.e. reduce immobility time. This assay was used in the present study for further investigating the involvement of the NOP receptor in depression states. In male Swiss mice, intracerebroventricular injection (i.c.v) of the novel NOP receptor antagonist, UFP‐101 (1–10 nmol) dose‐dependently reduced the immobility time (control 192 ± 14 s, UFP‐101 91 ± 15 s). The effect of 3 or 10 nmol UFP‐101 was fully or partially reversed, respectively, by the coadministration of 1 nmol N/OFQ, which was inactive per se. NOP receptor knockout mice showed a reduced immobility time compared with their wild‐type littermates (wild‐type 215 ± 10 s, knockout 143 ± 12 s). Moreover, i.c.v. injected UFP‐101 (10 nmol) significantly reduced immobility time in wild‐type mice but not in NOP receptor knockout animals. In conclusion, these results, obtained using a combined pharmacological and genetic approach, indicate that blockade of the N/OFQ‐NOP receptor signalling in the brain produces antidepressant‐like effects in the mouse FST. These findings support the NOP receptor as a candidate target for the development of innovative antidepressant drugs.
Nociceptin, acting through the opioid receptor-like 1 (ORL1) receptor, produces anti-nociception in several models of neuropathy. We examined the involvement of the ORL1 receptor system in the ...allodynia developed after sciatic nerve ligation. Allodynic rats were selected by the von Frey hair and treated intrathecally with nociceptin or morphine. The peptide induced dose-dependent anti-allodynic activities, while morphine was effective at the higher dose only. By the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, the two described ORL1 receptor isoforms were up-regulated in the allodynic animals, but unmodified in non-allodynic rats. Both short and long ORL1 receptor mRNA isoforms increased in the ipsilateral lumbar enlargement (by 50% and 100%, respectively), while 50% and 60% increases were found in the ipsilateral L5–L6 dorsal root ganglia, respectively. No significant changes were observed for either the nociceptin precursor or μ-opioid receptor expression. Thus, the ORL1 receptor system seems to regulate the mechano-allodynia that developed after nerve damage, suggesting its potential role in the treatment of neuropathic pain.
Cell-free fetal DNA in maternal plasma or serum is at present widely investigated as a source of fetal genetic material, both in studies of pregnancy-related disorders and in planning strategies for ...non-invasive prenatal diagnosis. Despite the number of trials already performed on the quantitation of fetal DNA, data about the amount of DNA at the beginning of pregnancy, in particular in the first trimester, remain limited. A new probe mapping on the deleted in azoospermia (DAZ) repetitive region of the Yq chromosome was designed for an early assessment of fetal DNA concentration in maternal serum. Among 57 pregnant women prospectively studied in their first trimester, fetal DNA was detected already by the 5th gestational week, with the analysis becoming reliable by the 8th week of gestation when a 100% accuracy in fetal sex determination was achieved. Moreover, in the three cases of pregnancy ending in fetal loss, the amount of fetal DNA apparently decreased before the abortion was diagnosed, whereas it consistently showed an increasing trend in normal pregnancies. Real-time PCR with the use of DAZ multilocus probe can efficiently quantitate free fetal DNA in the maternal serum at the beginning of pregnancy.
The effects of selective A(1) and A(2A) adenosine receptor compounds in two mouse models of acute nociception were studied: acetic acid-induced writhing and the hot plate assays. Stimulation of A(1) ...receptors by 2-chloro-N(6)-cyclopentyl-adenosine (CCPA, 0.01-0.1 mg/kg, i.p.; A(1)K(i)=6 nM) or blockade of A(2A) receptors by 5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo4,3-e-1,2,4-triazolo1,5-cpyrimidine (SCH58261, 1-10 mg/kg, i.p.; A(2)(A)K(i)=1.3 nM) produced anti-nociceptive effects. At the highest dose tested, CCPA and SCH58261 reduced the number of writhings by 79 and 99%, respectively. On the contrary, the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (A(1)K(i)=2.8 nM) and the A(2A) agonist 2-(4-2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine-hydrochloride (GGS21680) produced pro-nociceptive effects in both tests. These findings suggest for the first time that blockade of A(2A) adenosine receptors produces anti-nociceptive effects.
Ultraviolet (UV) light exposure is the primary factor responsible for skin photoaging, affecting all the skin layers, mainly through the production of reactive oxygen species (ROS), activation of ...inflammatory responses, and apoptosis. In keeping with this evidence, exogenous supplementation with dietary antioxidants has been shown to provide photoprotective benefits. Moreover, oral administration of hyaluronic acid (HA) has been proved to reduce the signs of aged skin, such as wrinkles, and increase hydration and elasticity. The combination of different biologically active substances in order to slow down the onset of skin aging could represent a promising preventive strategy against photoaging. In the present study, we investigated the effects of a dietary supplement (IALUTEC® RED), consisting of high‐molecular‐weight HA (HMW‐HA) combined with red orange extract (ROC‐Red Orange Complex®), in human fibroblasts exposed to ultra violet light B‐induced oxidative stress. Our study suggests that, in fibroblasts exposed to UVB light, IALUTEC® RED is active in decreasing both the inflammatory response and the generation of ROS, two events that are involved in skin photoaging.
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