Francisco Pellicer

Epileptogenesis and muscular hypertonic postictal phenomena induced by naloxone in intact cats.

Summary: Epileptogenesis produced by repeated i.p. administration of naloxone chloride and sensory stimulation (photoacoustic stimulation at 1,3, 10, and 15 Hz) every 15 min was studied in freely moving cats. The repeated administration of naloxone provoked some behavioral manifestations that resemble those produced by electrical amygdaloid kindling. Photoacoustic stimulation accentuated the manifestations. All the animals presented generalized behavioral seizures when total naloxone administration reached 80 mg/kg. None of the animals demonstrated postictal depression. These results suggest an inhibitory role of endogenous opioids and/or GABA in epileptogenesis.

Depressant Effects of Salvia divinorum Involve Disruption of Physiological Sleep

Although Salvia divinorum is traditionally known as a ‘mind‐altering’ or psychoactive herb used, among others things, as a tranquilizer, this property has not been validated with regard to its efficacy and safety. The objective of this study is to provide evidence for the sedative effects of S. divinorum and discriminate the nature of the responsible constituents by examining different experimental models. A battery of tests, including the open‐field, hole‐board, exploration cylinder, plus‐maze and sodium pentobarbital‐induced hypnosis potentiation, were used in mice after administration of non‐polar, medium polar and/or polar extracts of the plant (10, 30 and 100 mg/kg). Polysomnographic analysis in rats receiving an active medium polar extract (10 and 100 mg/kg) containing salvinorins was also assessed to study the effects of this plant on sleep architecture. All tested extracts produced significant sedative‐like responses, although those of the medium polar extract were more pronounced in mice. The sedative effect of this latter extract, which contains a mixture of salvinorins, caused fragmented sleep architecture in rats by diminishing rapid eye movement (REM) sleep and increased the quiet awake stage at 10 and 100 mg/kg. Our results provide evidence that S. divinorum exhibits sedative‐like depressant properties that alter physiological sleep architecture. Copyright

Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats

Flavonoids are natural compounds showing anti-hyperalgesic activity in models of pain. Diosmin is a compound poorly studied in the treatment of neuropathic pain. This study evaluates the anti-hyperalgesic actions of diosmin and possible mechanisms of action involved by using a neuropathic pain model in rats. Experimental neuropathic pain was induced by chronic constriction injury (CCI) in male Wistar rats, then aesthesiometric index and plantar tests were assessed to evaluate mechanical and thermal hyperalgesia, respectively, in order to explore the analgesic effects of acute and sub-chronic treatment with diosmin. The GABAA, 5-HT1A, D2-like and opioid receptors participation, as well as levels of TNF-α, IL-1β and IL-6, were evaluated in the spinal cord and sciatic nerve tissues after acute and subchronic diosmin administration. In addition, the presence of diosmin on cerebral samples was determined by UHPLC-MS analysis. Acute and sub-chronic treatment with diosmin significantly diminished the mechanical and thermal hyperalgesia induced by CCI in rats. This anti-hyperalgesic effects of diosmin were modified in the presence of naloxone (1mg/kg, i.p.) and haloperidol (0.1mg/kg, i.p.), but not by GABAA and 5-HT1A receptor antagonists. The anti-hyperalgesic effects of diosmin were also linked with reduced levels of TNF-α, IL-1β and IL-6. The presence of diosmin in the cerebral samples was confirmed by chromatographic analysis. In conclusion, our results provide evidence that diosmin produces significant anti-hyperalgesic effects acting at central level by an opioid and D2 dopaminergic receptors participation, and at peripheral level by reducing proinflammatory cytokines.

Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats

ETHNOPHARMACOLOGICAL RELEVANCE Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. AIM OF THE STUDY Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. MATERIAL AND METHODS Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. RESULTS Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. CONCLUSION The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.

Sleep architecture is altered in the reserpine-induced fibromyalgia model in ovariectomized rats

Graphical abstract Figure. No caption available. HighlightsParameters of the sleep ‐architecture are modified in the reserpine‐induced fibromyalgia model.Sleep alteration is a usefulness marker for fibromyalgia research.The antidepressant fluoxetine reverted sleep alterations in experimental fibromyalgia. &NA; Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome with various concomitant symptoms like sleep disorders. FM patients are mainly women and menopause might play an important role in the altered processing of somatosensory information. Adverse effects and moderated efficacy of drugs promote treatment discontinuation by patients. Animal models of FM report pain and depression‐like behaviors, but none of them have explored sleep disturbance as possible marker in the preclinic diagnostic. The aim of this study was to investigate alterations of the sleep architecture in the reserpine (RES)‐induced FM model in ovarectomized (OVX) rats. The behavioral thresholds of nociceptive response in the experimental FM were analyzed in a first block using muscle pressure, tactile response and allodynia to cold stimulus. In a second block, the sleep‐wake cycle was examined in a polysomnographic study. Groups (n = 8) consisted in: (a) no treatment, (b) RES vehicle, (c) RES alone, (d) RES + vehicle of fluoxetine (FLX, antidepressant reference drug), and (e) RES + FLX. Our results demonstrated that RES induced pain‐related behavior (50–70%) in OVX rats and altered sleep architecture by the increase of total wake time (38%), diminution of the no‐REM stage (SWS‐I 33% and SWS‐II 76%), and abolition of the REM sleep, effects that were partially reverted in the presence of FLX. In conclusion, our results support the face validity of the RES‐induced pain‐related behavior as FM model showing nociceptive behavioral responses associated to sleep alterations observed as symptoms in FM patients; thus, these evidences substantiate its usefulness to look for alternatives of treatment for FM symptoms.