Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis: role of mast cells.

The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in 'a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg-1 ·d-1, orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P<0.01), vessel number (P< 0.01), chymase (P< 0.05), NGF (P<0.05), VEGF (P< 0.01), and Flk-1 (P< 0.01) expression in cysts and NGF expression in DRG (P< 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics

Impact of migraine on fibromyalgia symptoms

Background: Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms. Methods: Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: −electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, −pressure pain thresholds in tender points (TePs), −number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups (n.49, n.39). 1-way ANOVA was applied to test trends among groups, Student’s t-test for paired samples was used to compare pre and post-treatment values. Results: The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: p &lt; 0.0001). FMS monthly flares were progressively higher in FMS, FMS + M1 and FMS + M2 (p &lt; 0.0001); most flares (86–87 %) occurred within 12 h from a migraine attack in co-morbid patients (p &lt; 0.0001). Effective migraine prophylaxis vs no prophylaxis also produced a significant improvement of FMS symptoms (decreased monthly flares, increased pain thresholds)(0.0001 &lt; p &lt; 0.003). Conclusions: Co-morbidity between fibromyalgia and migraine involves heightened somatic hyperalgesia compared to one condition only. Increased migraine frequency – with shift towards chronicity – enhances both hyperalgesia and spontaneous FMS pain, which is reversed by effective migraine prophylaxis. These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS

The Assessment of Post-Vasectomy Pain in Mice Using Behaviour and the Mouse Grimace Scale

Background: Current behaviour-based pain assessments for laboratory rodents have significant limitations. Assessment of facial expression changes, as a novel means of pain scoring, may overcome some of these limitations. The Mouse Grimace Scale appears to offer a means of assessing post-operative pain in mice that is as effective as manual behavioural-based scoring, without the limitations of such schemes. Effective assessment of post-operative pain is not only critical for animal welfare, but also the validity of science using animal models. Methodology/Principal Findings: This study compared changes in behaviour assessed using both an automated system (‘‘HomeCageScan’’) and using manual analysis with changes in facial expressions assessed using the Mouse Grimace Scale (MGS). Mice (n = 6/group) were assessed before and after surgery (scrotal approach vasectomy) and either received saline, meloxicam or bupivacaine. Both the MGS and manual scoring of pain behaviours identified clear differences between the pre and post surgery periods and between those animals receiving analgesia (20 mg/kg meloxicam or 5 mg/kg bupivacaine) or saline post-operatively. Both of these assessments were highly correlated with those showing high MGS scores also exhibiting high frequencies of pain behaviours. Automated behavioural analysis in contrast was only able to detect differences between the pre and post surgery periods. Conclusions: In conclusion, both the Mouse Grimace Scale and manual scoring of pain behaviours are assessing th

Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab [Corrigendum]

Giamberardino MA, Affaitati G, Costantini R, et al. J Pain Res. 2017;10:2751&ndash;2760.On page 2756, left column, lines 7 and 8: &ldquo;Patients who previously had failed two preventative medications were excluded.&rdquo; should have been: &ldquo;Patients who previously had failed more than two preventive medications were excluded.&rdquo;On page 2756, right column, lines 41&ndash;43: &ldquo;There was a difference of &minus;1.1 days in the main change in monthly migraine days between 70 mg erenumab group and placebo.&rdquo; should have been: &ldquo;There was a difference of &minus;2.5 days in the mean change in monthly migraine&nbsp; days between 70 mg erenumab group and placebo.&rdquo;Read the original article &nbsp

Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab

Maria Adele Giamberardino,1,* Giannapia Affaitati,1,* Raffaele Costantini,2 Francesco Cipollone,3,* Paolo Martelletti4,* 1Department of Medicine and Science of Aging, Headache Center, Geriatrics Clinic and Ce.S.I.-Met, &ldquo;G. D&rsquo;Annunzio&rdquo; University of Chieti, Chieti, Italy; 2Department of Medical, Oral and Biotechnological Sciences, Institute of Surgical Pathology, &ldquo;G. D&rsquo;Annunzio&rdquo; University of Chieti, Chieti, Italy; 3Department of Medicine and Science of Aging, Medical Clinic and Ce.S.I.-Met, &ldquo;G. D&rsquo;Annunzio&rdquo; University of Chieti, Chieti, Italy; 4Department of Clinical and Molecular Medicine, Regional Referral Headache Center, Sant&rsquo;Andrea Hospital, Sapienza University of Rome, Rome, Italy *These authors contributed equally to this work Abstract: Migraine is a highly disabling neurological condition, and preventative treatment still remains problematic, due to aspecificity of the majority of the currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP) plays a crucial role in migraine pathophysiology; agents aimed at blocking its activity have, therefore, been developed in recent years, among which are monoclonal antibodies (mAbs) against CGRP, to prevent migraine. Erenumab is the only mAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. This review will report on the most recent data on erenumab characteristics and on the results of clinical trials on its employment in the prevention of episodic migraine (4&ndash;14 monthly migraine days): one Phase II and two Phase III trials (completed) and one Phase III trial (ongoing). Monthly subcutaneous administration (70 mg or 140 mg) of erenumab vs placebo for 3&ndash;6 months showed significantly higher efficacy in reducing the mean monthly number of migraine days and the use of migraine-specific medication, and in decreasing physical impairment and impact of migraine on everyday activities (P&lt;0.001). A favorable safety profile was demonstrated by the lack of significant differences in the occurrence of adverse events in erenumab-treated vs placebo-treated patients. Global results so far obtained point to erenumab as a new promising candidate for the preventative treatment of episodic migraine. Licence applications for erenumab were recently submitted to the Food and Drug Administration in the USA and European Medicines Agency in Europe (May/June 2017). Keywords: erenumab, episodic migraine, CGRP, CGRP recepto