Antihyperalgesic Effect of Eschscholzia Californica in Rat Models of Neuropathic Pain

Eschscholzia californica Cham. (Papaveraceae) is traditionally used by the Indians as a medicinal plant for its anxiolytic, anticonflict, analgesic and sedative properties. The mechanisms of action for the sedative and anxiolytic activities have not been clearly established and so to further investigate the pharmacological profile of E. californica in some painful conditions, a 70% v/v ethanol extract, DERnative=5:1, was tested in rat models of neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), with chemotherapeutic oxaliplatin, and osteoarthritis caused by intrarticular injection of monoiodoacetate. In the CCI model evaluated in the rat paw-pressure test, the examined extract (100 mg kg−1 p.o.) showed an antihyperalgesic effect. Eschscholzia extract, after single injection at a dose of 100–300 mg kg−1 p.o., produced also a statistically significant decrease of pain perception on hyperalgesia induced by oxaliplatin and osteoarthritis, while in the same condition gabapentin did not display any antihyperalgesic effect. Furthermore, in the range of antihyperalgesic doses, the extract was efficacious in the hot-plate (thermal stimulus) and carrageenan tests (inflammatory model) without producing any behavioral impairment, as evaluated by the Irwin test. The analgesic effect exhibited by Eschscholzia extract in the mouse hot-plate test was not antagonized by naloxone, indicating that opioid neurotransmission is not involved in the effect. The above reported results suggest that a 70% (v/v) ethanol dried extract (DERnative=5:1) of E. californica might represent a promising product for the therapy of acute and chronic pain

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003–9 nmol per mouse intracerebroventricularly [i.c.v.]) ameliorated memory functions, whereas the RyR antagonist ryanodine (0.0001–1 nmol per mouse i.c.v.) induced amnesia in the mouse passive avoidance test. The role of the type 1, 2, and 3 RyR isoforms in memory processes was then evaluated by inhibiting the expression of the three RyR proteins in the mouse brain. A selective knockdown of the RyR isoforms was obtained by the i.c.v. administration of antisense oligonucleotides (aODNs) complementary to the sequence of RyR1, RyR2 and RyR3 proteins, as demonstrated by immunoblotting experiments. RyR1 (5–9 nmol per mouse i.c.v.) knockdown mice did not show any memory dysfunction. Conversely, RyR2 (1–7 nmol per mouse i.c.v.) and RyR3 (1–7 nmol per mouse i.c.v.) knockdown animals showed an impairment of memory processes. This detrimental effect was temporary and reversible, disappearing 7 d after the end of the aODN treatment. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous mobility and inspection activity, as revealed by the hole-board test. In conclusion, the lack of any involvement of cerebral RyR1 was demonstrated. These findings also showed the involvement of type 2 and type 3 RyR in the modulation of memory functions identifying these cerebral RyR isoforms as critical targets underlying memory processes

Feedback and the Mini Clinical Evaluation Exercise

We studied the nature of feedback given after a miniCEX. We investigated whether the feedback was interactive; specifically, did the faculty allow the trainee to react to the feedback, enable self-assessment, and help trainees to develop an action plan for improvement. Finally, we investigated the number of types of recommendations given by faculty. One hundred and seven miniCEX feedback sessions were audiotaped. The faculty provided at least 1 recommendation for improvement in 80% of the feedback sessions. The majority of the sessions (61%) involved learner reaction, but in only 34% of the sessions did faculty ask for self-assessment from the intern and only 8% involved an action plan from the faculty member. Faculty are using the miniCEX to provide recommendations and often encourage learner reaction, but are underutilizing other interactive feedback methods of self-assessment and action plans. Programs should consider both specific training in feedback and changes to the miniCEX form to facilitate interactive feedback

NR2B expression in rat DRG is differentially regulated following peripheral nerve injuries that lead to transient or sustained stimuli-evoked hypersensitivity

Following injury, primary sensory neurons undergo changes that drive central sensitization and contribute to the maintenance of persistent hypersensitivity. NR2B expression in the Dorsal root ganglia (DRG) has not been previously examined in neuropathic pain models. Here we investigated if changes in NR2B expression within the DRG are associated with hypersensitivities that result from peripheral nerve injuries. This was done by comparing the NR2B expression in the DRG derived from two modalities of the spared nerve injury (SNI) model, since each variant produces different neuropathic pain phenotypes. Using the electronic von Frey to stimulate the spared and non-spared regions of the hindpaws, we demonstrated that sural-SNI animals develop sustained neuropathic pain in both regions while the tibial-SNI animals recover. NR2B expression was measured at Day 23 and Day 86 post-injury. At both days sural-SNI displays strong hypersensitivity. At Day 23 and Day 86, tibial-SNI respectively displays 50% and 100% recovery from post-injury-induced hypersensitivity. In tibial-SNI at Day 86, but not at Day 23 the perinuclear region of the neuronal somata displayed an increase in NR2B protein. This retention of NR2B protein within the perinuclear region, which will render them nonfunctional, correlates with the recovery observed in tibial-SNI. In sural SNI at Day 86 displayed an increase in NR2B mRNA which correlates with the development of sustained hypersensitivity following sural-SNI. The increase in NR2B mRNA was not associated with an increase in NR2B protein within the neuronal somata. The latter may result from a decrease in kinesin Kif17, since Kif17 mediates NR2B transport to the soma’s plasma membrane. In both SNIs, microglia/macrophages showed a transient increase in NR2B protein detected at Day 23 but not at Day 86; which correlates with the initial post-injury induced hypersensitivity in both SNIs. In tibial-SNI at Day 86, but not at Day 23 satellite glia cells (SGCs) displayed an increase in NR2B protein. This study is the first to characterize of cell-specific changes in NR2B expression within the DRG following peripheral nerve injury. We discuss how the observed NR2B changes in DRG can contribute to the different neuropathic pain phenotypes displayed by each SNI variant

Synthesis, in vitro, and in vivo biological evaluation and molecular docking simulations of chiral alcohol and ether derivatives of the 1,5-diarylpyrrole scaffold as novel anti-inflammatory and analgesic agents

Following our previous research on anti-inflammatory drugs (NSAIDs), we report here the synthesis of chiral 1,5-diarylpyrroles derivatives that were characterized for their in vitro inhibitory effects toward cyclooxygenase (COX) isozymes. Analysis of enzymatic affinity and COX-2 selectivity led us to the selection of one compound (+/-)-10b that was further tested in vitro in the human whole blood (HWB) and in vivo for its anti-inflammatory activity in mice. The affinity data have been rationalized through docking simulations. (C) 2008 Elsevier Ltd. All rights reserved