Neuropharmacology
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γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. ⋯ BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice.
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Chronic psychosocial isolation stress (CPSI) modulates glucocorticoid receptor (GR) functioning in Wistar male rat hippocampus (HIPPO) through alteration of nuclear GR phosphorylation and its upstream kinases signaling, which parallels animal depressive-like behavior. The current study investigated potential gender specificities regarding the effect of chronic therapy by an antidepressant fluoxetine (FLU) on GR signaling in HIPPO and depressive-like behavior in CPSI animals. FLU was administrated to female and male naïve or CPSI rats for 21 days and GR protein, its phosphorylation status and upstream kinases, as well as GR and BDNF mRNA were followed in HIPPO together with animal serum corticosterone (CORT) and depressive-like behavior. ⋯ In contrast, FLU exhibited gender-specific effect on BDNF mRNA in CPSI animals, by increasing it in females, but not in males. In spite of normalization the total nuclear GR level upon FLU treatment in both gender, down-regulation of GR mRNA is possibly maintained through prevalence of pGR232 isoform only in males. The gender-specific alterations of pGR232-Cdk5 signaling and BDNF gene expression in HIPPO and normalization of depressive-like behavior upon FLU treatment distinguishes this signaling pathway as potential future antidepressant target for gender-specific therapy of stress related mood disorders.
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Peroxisome proliferator-activated receptor gamma (PPARγ) is emerging as a new pharmacotherapeutic target for chronic pain. When oral (3-30 mg/kg/day in chow for 7 wk) or twice-daily intraperitoneal (1-10 mg/kg/day for 2 wk) administration began before spared nerve injury (SNI), pioglitazone, a PPARγ agonist, dose-dependently prevented multiple behavioral signs of somatosensory hypersensitivity. The highest dose of intraperitoneal pioglitazone did not produce ataxia or reductions in transient mechanical and heat nociception, indicating that inhibitory effects on hypersensitivity were not secondary to adverse drug-induced behaviors or antinociception. ⋯ Intraperitoneal pioglitazone significantly reduced the nerve injury-induced up-regulation of cd11b, GFAP, and p-p38 in the dorsal horn, indicating a mechanism of action involving spinal microglia and/or astrocyte activation. Oral pioglitazone significantly reduced touch stimulus-evoked phospho-extracellular signal-related kinase (p-ERK) in lamina I-II, indicating a mechanism of action involving inhibition of central sensitization. We conclude that pioglitazone reduces spinal glial and stimulus-evoked p-ERK activation and that PPARγ activation blocks the development of and reduces established neuropathic pain.
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Tyrosine phosphorylation of N-methyl-d-aspartate (NMDA) subtype glutamate receptors by Src-family protein tyrosine kinases (SFKs) plays a critical role in spinal sensitization. Besides SFKs, the tyrosine phosphorylation levels of proteins are also determined by protein tyrosine phosphatases (PTPs). However, whether PTPs are involved in spinal nociceptive processing is largely unknown. ⋯ As a result, PTPs inhibition largely suppressed Src-mediated NR2B phosphorylation at Tyr1472 and reduced the synaptic concentration of NR2B receptors in spinal dorsal horn of NMDA-treated rats. Importantly, intraplantar injection of Complete Freund's Adjuvant (CFA) naturally activated spinal PTPs to initiate Src signaling, because PTPs inhibition significantly repressed Src activity, reduced Src phosphorylation of NR2B, decreased NR2B synaptic accumulation and eventually ameliorated inflammatory pain. These data indicated an important role played by spinal PTPs in inducing Src-dependent NR2B receptor hyperfunction and suggested that PTPs inhibition might represent an effective strategy for the treatment of inflammatory pain.
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In search of a basis for the impressive potency of an endoprotease that cleaves SNAP-25, botulinum neurotoxin type A (BoNT/A), in treating numerous diseases due to hyper-active autonomic nerves, truncation of its target and inhibition of neurotransmission were studied in rat sympathetic neurons. Tetrodotoxin-sensitive spontaneous cholinergic neurotransmission was blocked >80% by 1 pM BoNT/A despite cleaving <20% of the SNAP-25. A maximum cleavage of ∼60% SNAP-25 could be achieved with >1 nM BoNT/A, despite an absence of non-cleavable SNAP-25 in the detergent-solubilised neurons. ⋯ On the other hand, partial cleavage by the BoNT/A protease persisted upon replacing its HC with counterparts from BoNT/E or BoNT/B. Moreover, limited cleavage of SNAP-25 was conferred onto the protease from BoNT/E when fused to the N-terminus of BoNT/A. Thus, the BoNT/A protease is uniquely well-adapted for selectively inactivating the SNAP-25 directly involved in neurotransmission; this together with the toxin's acceptor and its target being localised on the peri-somatic boutons likely contribute to its exceptional therapeutic utility in the clinic.