Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy : pain relief and neuroprotection share a PPAR-alpha-mediated mechanism

Peer reviewedPublisher PD

Contribution of G inhibitory protein alpha subunits in paradoxical hyperalgesia elicited by exceedingly low doses of morphine in mice.

Aims: Although morphine, at higher doses, induces analgesia, it may also enhance sensitivity to pain at extremely low doses as shown in studies for testing an animal's sensitivity to pain. We used an antisense approach capable of selectively down-regulating in vivo G(i)(G inhibitory protein),G(o) and G(s) members of the G(alpha), sub-family protein subunits in order to establish if these proteins might be implicated in the effects induced by extremely low morphine doses on acute thermonociception. Main methods: Mice pretreated with a morphine hyperalgesic dose (1 mu g/kg) were submitted to hot plate test after pre-treatment with antisense oligodeoxynucleotides (aODNs) targeting G(i alpha), G(o alpha) and G(s alpha) regulatory proteins. The association of G-protein (guanine nucleotide-binding regulatory protein) coupled receptors with G protein was investigated using co-immunoprecipitation procedure. Key findings: The downregulation of the G(i alpha 1-3) and G(o alpha 1) proteins reversed the licking latency responses induced by 1 mu g/kg morphine administration toward the basal value whereas downregulation of the G(o alpha 2) and G(s alpha) proteins did not significantly modify the hyperalgesic response. Significance: These results suggest that G inhibitory proteins play a role in the production of low dose evoked morphine hyperalgesia in mouse. Immunoprecipitation studies revealed that both mu opioid receptor (mu OR) and alpha(2) adrenoreceptor (alpha(2) AR) are bound to G inhibitory proteins in hyperalgesic response to morphine extremely low dose. Both mu OR and alpha(2) AR appear to be necessary for low morphine dose induced hyperalgesic response through G inhibitory proteins. (C) 2011 Elsevier Inc. All rights reserved

Role of potassium channels in the antinociception induced by agonists of alpha2-adrenoceptors

1. The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K(+) channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test. 2. Pretreatment with pertussis toxin (0.25 μg per mouse i.c.v.) 7 days before the hot-plate test, prevented the antinociception induced by both clonidine (0.08–0.2 mg kg(−1), s.c.) and guanabenz (0.1–0.5 mg kg(−1), s.c.). 3. The administration of the K(ATP) channel openers minoxidil (10 μg per mouse, i.c.v.), pinacidil (25 μg per mouse, i.c.v.) and diazoxide (100 mg kg(−1), p.o.) potentiated the antinociception produced by clonidine and guanabenz whereas the K(ATP) channel blocker gliquidone (6 μg per mouse, i.c.v.) prevented the α(2) adrenoceptor agonist-induced analgesia. 4. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K(+) channel, at the dose of 2.0 nmol per single i.c.v. injection, prevented the antinociception induced by both clonidine and guanabenz in comparison with degenerate oligonucleotide (dODN)-treated mice. 5. The administration of the Ca(2+)-gated K(+) channel blocker apamin (0.5–2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia. 6. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota-rod test. 7. The present data demonstrate that both K(ATP) and mKv1.1 K(+) channels represent an important step in the transduction mechanism underlying central antinociception induced by activation of α(2) adrenoceptors

New perspectives in the pathophysiology and treatment of pain in patients with dry eye disease

Ocular discomfort and eye pain are frequently reported by patients with dry eye disease (DED), and their management remains a real therapeutic challenge for the Ophthalmologist. In DED patients, injury at the level of each structure of the ocular surface can determine variable symptoms, ranging from mild ocular discomfort up to an intolerable pain evoked by innocuous stimuli. In refractory cases, the persistence of this harmful signal is able to evoke a mechanism of maladaptive plasticity of the nervous system that leads to increased pain responsiveness. Peripheral and, sub-sequently, central sensitization cause nociceptor hyperexcitability and persistent pain perception that can culminate in the paradoxical situation of perceiving eye pain even in the absence of ocular surface abnormalities. Effective therapeutic strategies of these cases are challenging, and new options are desirable. Recently, a theoretical novel therapeutic approach concerns enkephalins thanks to the evidence that eye pain sensations are modulated by endogenous opioid peptides (enkephalins, endorphins and dynorphins). In this regard, new topical agents open up a new theoretical scenario in the treatment of ocular discomfort and eye pain in the setting of DED, such as, for example, a multimolecular complex based on proteins and glycosaminoglycans also containing opiorphin that may assist the physiological pain-relieving mechanism of the eye

The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, prochlorperazine and caffeine, compared to sumatriptan, in an in vivo model.

A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan. The mice model of abdominal constriction test induced by an i.p. injection of a 0.6% solution of acetic acid was used. The study showed that Indoprocaf (a fixed combination of indomethacin 1 mg/kg, prochlorperazine 1 mg/kg and caffeine 3 mg/kg, s.c.) and sumatriptan (20 mg/kg, s.c.) exert their central antinociceptive action independently from the Gi proteins. In addition, the antinociceptive efficacy of Indoprocaf in this study was statistically superior to that of sumatriptan. This study also showed that the single active ingredients of Indoprocaf, indomethacin (1 mg/kg, s.c.), prochlorperazine (1 mg/kg, s.c.) and caffeine (3 mg/kg, s.c.), were able to exert their central antinociceptive action independently from the Gi proteins. However, Indoprocaf at analgesic doses was able to abolish almost completely the abdominal constrictions, with a statistically higher efficacy compared to the single active ingredients, showing an important synergic effect of Indoprocaf. This synergic effect was evident not only when Gi proteins activity was abolished by PTX, but also under control condition, when Gi proteins were active. This study suggests that the central antinociceptive action induced by antimigraine drugs is independent from Gi proteins