Aitziber Mendiguren - Academia.edu (original) (raw)

Papers by Aitziber Mendiguren

Frontiers in Pharmacology

The pharmacological profile of cannabigerol (CBG), which acid form constitutes the main precursor... more The pharmacological profile of cannabigerol (CBG), which acid form constitutes the main precursor of the most abundant cannabinoids, has been scarcely studied. It has been reported to target α2-adrenoceptor and 5-HT1A receptor. The locus coeruleus (LC) and the dorsal raphe nucleus (DRN) are the main serotonergic (5-HT) and noradrenergic (NA) areas in the rat brain, respectively. We aimed to study the effect of CBG on the firing rate of LC NA cells and DRN 5-HT cells and on α2-adrenergic and 5-HT1A autoreceptors by electrophysiological techniques in male Sprague-Dawley rat brain slices. The effect of CBG on the novelty-suppressed feeding test (NSFT) and the elevated plus maze test (EPMT) and the involvement of the 5-HT1A receptor was also studied. CBG (30 μM, 10 min) slightly changed the firing rate of NA cells but failed to alter the inhibitory effect of NA (1–100 µM). However, in the presence of CBG the inhibitory effect of the selective α2-adrenoceptor agonist UK14304 (10 nM) was ...

Background and purpose: Previous studies have suggested a regulation of 5-hydroxytryptamine (5-HT... more Background and purpose: Previous studies have suggested a regulation of 5-hydroxytryptamine (5-HT) neurons by the endocannabinoid system. The aim of our work was to examine the effect of two CB1 receptor antagonists, SR141716A (rimonabant, Sanofi-Synthélabo Recherche, Montpellier, France) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, Tocris Cookson, Bristol, UK), on the firing rate of dorsal raphe nucleus (DRN) neurons. Experimental approach: Single-unit extracellular recordings were performed to study the effect of CB1 receptor antagonists in slices of the DRN from rat brain. Key results: Rimonabant (1 mM) and AM251 (1 mM) decreased the firing rate of about 50% of all the recorded DRN 5-HT cells. The GABAA receptor antagonist picrotoxin (20 mM) (Sigma) prevented and also reversed the inhibitory effect of rimonabant (1 mM) and AM251 (1 mM), suggesting that CB1 receptors regulate 5-HT neurons through the GABAergic system. However, the CB1/CB2 receptor agonist R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol[1,2,3-de]-1,4-benzoxazinyl]-(1naphthalenyl) methanone mesylate salt (10 mM) (WIN55212-2, Sigma, St. Louis, MO, USA) failed to change the firing activity of non-5-HT (presumably GABAergic) neurons in the DRN. The endocannabinoid N-(2-hydroxyethyl)-5Z,8Z,11Z,14Zeicosatetraenamide (anandamide, Tocris Cookson) (10 mM) also inhibited the firing activity of a number of 5-HT neurons, but this inhibition was not blocked by rimonabant (1 mM) or AM251 (1 mM), and the stable analogue R-(+) N-(2-hydroxy-1methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (methanandamide, Tocris Cookson) (10 mM) did not mimic this effect. The selective CB1 receptor agonist arachidonoyl-2-chloroethylamide (ACEA) (1 mM) only slightly increased the firing rate of DRN 5-HT cells. Conclusions and implications: These results suggest a tonic/constitutive regulation of DRN 5-HT neurons by the endocannabinoid system, which may occur through a CB1 receptor-mediated inhibition of the GABAergic system. The inhibitory effect of anandamide may be mediated through a CB1 receptor-independent mechanism.

Frontiers in Pharmacology

Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits sev... more Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects via the 5-HT1A receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT1A receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT1A autoreceptors have not been characterized. Our aim was to study the effect of CBD on the firing activity of DRN 5-HT cells and the 5-HT1A autoreceptor activation by electrophysiological and calcium imaging techniques in male Sprague–Dawley rat brain slices. Perfusion with CBD (30 μM, 10 min) did not significantly change the firing rate of DRN 5-HT cells or the inhibitory effect of 5-HT (50–100 μM, 1 min). However, in the presence of CBD (30 μM, 10 min), the inhibitory effects of 8-OH-DPAT (10 nM) and ipsapirone (100 nM) were reduced by 66% and 53%, respectively. CBD failed to reverse ipsapirone-induced inhib...

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd edition, 2017

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd edition, 2017

Introduction: Neuropathic pain is the pain that arises as a direct consequence of a lesion or dis... more Introduction: Neuropathic pain is the pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system. It could be central (postraumatic pain, multiple sclerosis, pain due to spinal cord injury, pain related to acquired immune deficiency syndrome, AIDS) or peripheral (post-herpetic neuralgia or diabetic peripheral neuropathy). Classical analgesic drugs have failed to show good efficacy for the treatment of neuropathic pain. For that reason, antiepileptic drugs such as pregabalin have been introduced for the treatment of this pain. Over the last years, pregabalin has been used to relieve neuropathic pain due to all causes leading to its over prescription. Objective: The aim of this research was to analyse the efficacy of pregabalin for the treatment of different types of neuropathic pain. Methodology: Randomized placebo controlled clinical trials were analysed following systematic methodological procedure. Results: In clinical trials that include pa...

Prostanoids are known to regulate several physiological functions and to play an important role i... more Prostanoids are known to regulate several physiological functions and to play an important role in certain pathophysiological situations such as inflammation. Prostaglandin E2 receptors (EP) are members of the G protein-coupled receptor superfamily. Four subtypes have been described: EP2 and EP4 (coupled to Gs proteins) and EP1 and EP3 (coupled to Gi/o proteins). To date, the function of the prostanoid system in the brain has not been well characterized. The locus coeruleus (LC), the main noradrenergic nucleus in the brain, has been described to express the EP3 receptor. The aim of this study was to characterize the functional relevance of EP3 receptors in the LC by single-unit extracellular recordings in rat brain slices. We performed concentration-effect curves for different endogenous derivatives and selective agonists of EP3 receptors. Thus, increasing concentrations of the EP3/EP1 agonist sulprostone (0.3-80 nM) fully inhibited the neuronal activity of LC cells, with an EC50 va...

EKAIA Euskal Herriko Unibertsitateko Zientzia eta Teknologia Aldizkaria, 2021

Loezinak, loak hartzeko edo mantentzeko zailtasunari, behar baino lehenago esnatzeari zein indarb... more Loezinak, loak hartzeko edo mantentzeko zailtasunari, behar baino lehenago esnatzeari zein indarberritzailea ez den loa edukitzeari egiten dio erreferentzia. Loezinak erritmo zirkadianoaren lo-esnatzearen alterazioak (adibidez, loaldi atzeratuaren sindromea edo lan txandekin lotutako loezina) eta ez-REM loaren esnatze asaldurak (somnanbulismoa, gaueko ikarak edo amesgaiztoak, besteak beste) barnebiltzen ditu. Loezinaren tratamendurako gehien erabiltzen diren farmakoek (bentzodiazepinek eta Z-hipnotikoek) eragin kaltegarri ugari dituzte eta epe luzera erabiltzeko ez dira gomendagarriak. Horregatik, loezina tratatzeko, ustez segurtasun hobea eta eraginkortasun bera duten alternatibak merkaturatu dira, adibidez, melatonina. Azken urteotan, melatoninaren erabilera asko handitu da eta adin guztietako pazienteengan loezin mota ugari arintzeko erabili izan da, baina ez dago argi erabilera hori ebidentzian oinarrituta dagoen. Horregatik, lan honen helburua gaixotasunekin erlaziorik ez zuen ...

Advances in Experimental Medicine and Biology, 2021

Background: Although a poor diet is the number one risk factor for early death in the United Stat... more Background: Although a poor diet is the number one risk factor for early death in the United States and globally, physicians receive little to no training in dietary interventions and lack confidence counseling patients about lifestyle modifications. Innovative, interprofessional strategies to address these gaps include the emergence of culinary medicine, a hands-on approach to teaching the role of food in health outcomes. We sought to assess the impact of a culinary medicine elective on counseling confidence, awareness of an evidence-based approach to nutrition, and understanding of the role of interprofessional teamwork in dietary lifestyle change among medical students at one undergraduate medical school. Methods: We administered pre-and post-course surveys to two cohorts of medical students (n = 64 at pre-test and n = 60 at post-test) participating in a culinary medicine enrichment elective. Chi-square analysis was used to assess the relationship between participation in the course and a positive response to each survey item. Results: Compared with the baseline, students participating in culinary medicine were more likely to feel confident discussing nutrition with patients (29% vs 92%; p < 0.001), to feel familiar with the Mediterranean diet (54% vs. 97%; p < 0.001), and to understand the role of dietitians in patient care (37% vs. 93%; p < 0.001). Conclusions: Culinary medicine shows promise as an impactful educational strategy among first-year medical students for increasing counseling confidence, promoting familiarity with evidence-based nutrition interventions, and augmenting understanding of the role of interprofessional engagement to address lifestyle-related disease.

Advances in Experimental Medicine and Biology, 2021

British journal of pharmacology, Jan 7, 2017

Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opio... more Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opioid tolerance that contributes to inefficient recycling of opioid responses. We aimed to characterize the functional turnover of μ receptors in the noradrenergic nucleus locus coeruleus (LC). We measured opioid effect by single-unit extracellular recordings of LC neurons from rat brain slices. Immunocytochemical techniques were used to evaluate μ receptor trafficking. After near-complete, irreversible μ receptor inactivation with β-funaltrexamine (β-FNA), opioid effect spontaneously recovered in a rapid and efficacious manner. In contrast, α2 -adrenoceptor-mediated effect hardly recovered after receptor inactivation with the irreversible antagonist EEDQ. When the recovery of opioid effect was tested after various inactivating time schedules, we found that the longer the β-FNA pre-exposure, the less efficient and slower the functional μ receptor turnover became. Interestingly, μ receptor t...

EKAIA Euskal Herriko Unibertsitateko Zientzi eta Teknologi Aldizkaria, 2017

Cannabis sativa landarean kannabidiola, kannabigerola edo Δ9-tetrahidrokannabibarina bezalako kan... more Cannabis sativa landarean kannabidiola, kannabigerola edo Δ9-tetrahidrokannabibarina bezalako kannabinoide ez-psikoaktiboak aurki daitezke. Oro har, kannabinoide horiek kannabinoideen hartzaileekiko (CB) afinitate txikia dutenez, ez daukate kannabinoide klasikoek (bereziki Δ9-THCak) duten aktibitate psikoaktiboa. Gizakietan eta animalietan kannabinoide ez-psikoaktiboekin egindako lehenengo ikerketek horien propietate terapeutikoak frogatu dituzte. Efektu horiek azaltzeko itu eta mekanismo desberdinak proposatu dira, besteak beste, hartzaile serotonergikoen aktibazioa edota entzima desberdinen modulazioa.

Neuroscience Letters, 2004

... Statistical evaluation was performed by one-way ANOVA followed by Dunnet's test (for com... more ... Statistical evaluation was performed by one-way ANOVA followed by Dunnet's test (for comparisons between independent groups) or by the paired Student's t-test (for comparisons within the same cells) using the computer program GraphPad Prism v. 3.00 for Windows ...

Neuropharmacology, 2012

A functional interaction between serotonergic and noradrenergic systems has been shown in the loc... more A functional interaction between serotonergic and noradrenergic systems has been shown in the locus coeruleus (LC). Noradrenaline (NA) levels in the prefrontal cortex (PFC) are dependent on the firing rate of LC neurons, which is controlled by a 2 adrenoceptors (a2ADR). The aim of the present study was to investigate the role of 5-HT 3 receptors (5HT3R) in the modulation of central noradrenergic activity. We measured extracellular NA concentrations in the LC and PFC by dual-probe microdialysis in awake rats and the firing rate of LC neurons by electrophysiological techniques in vitro. Administration of the 5HT3R agonists SR57227 (1e100 mM) and m-chlorophenylbiguanide (mCPBG, 1e100 mM) into the LC increased NA in this nucleus (E max ¼ 675 AE 121% and E max ¼ 5575 AE 1371%, respectively) and decreased NA in the PFC (E max ¼ À49 AE 6% and E max ¼ À25 AE 11%, respectively). Administration of the 5HT3R antagonist Y25130 (50 mM) into LC attenuated SR57227 effect in the LC (E max ¼ 323 AE 28%) and PFC (E max ¼ À37 AE 7%). The a2ADR antagonist RS79948 (1 mM) blocked the SR57227 effect in the PFC but it did not change the effect in the LC (E max ¼ 677 AE 202%). In electrophysiological assays, both mCPBG (1e10 mM) and SR57227 (1e10 mM) reduced the firing rate of about 50% of tested LC neurons (maximal effect ¼ À37 AE 2% and À31 AE 4%, respectively); this effect was partially blocked by Y25130 (50 mM). Administration of RS79948 (1 mM) reversed the inhibition induced by mCPBG. Competition radioligand assays against [ 3 H]UK14304 and [ 3 H]RX821002 (a2ADR selective drugs) in the rat brain cortex showed a very weak affinity of SR57227 for a2ADR, whereas the affinity of mCPBG for a2ADR was 17-fold higher than that of SR57227 for a2ADR. The present results suggest that 5HT3R stimulate NA release in the LC, which promotes simultaneously a decrease in the firing rate of LC neurons through a2ADR and then a decrease of NA release in terminal areas such as the PFC.

Osagaiz: osasun-zientzien aldizkaria, Dec 17, 2017

Ehunetako benetako kaltearekin edo kalte potentzialarekin erlazionatutako esperientzia sentsorial... more Ehunetako benetako kaltearekin edo kalte potentzialarekin erlazionatutako esperientzia sentsorial eta emozional desatsegina da mina, eta sailka daiteke jatorriaren arabera (nozizeptiboa, neuropatikoa), larritasunaren arabera (arina, larria) zein iraupenaren arabera ere (akutua, kronikoa). Oro har, gaur egun mina tratatzeko merkaturatuta dauden farmakoak eraginkorrak dira, baina epe luzera erabiltzean arazoak ager daitezke. Adibidez, opiazeoak analgesiko indartsuak diren arren, kronikoki ematean haien eraginkortasuna txikitu daiteke eta eragin desiragaitzak agertu. Estatistikak dio populazioaren % 15ek min kronikoa jasaten duela. Min kronikoak norbanakoa ezindu dezake eta hura arintzea zaila gerta daiteke. Horregatik, mina tratatzeko estrategia eta itu berrien ikerketak beharrezkoak dira. Ikergai dagoen itu bat sistema kannabinoidea da. Barneko kannabinoideak giza gorputzak ekoizten dituen molekulak dira, zeinek kannabinoide-hartzaileei (CB) lotuz funtzio fisiologiko ugari erregulatzen dituzten, mina adibidez. Cannabis generoko landareetan aurki daitezkeen landare-kannabinoideek barneko sistema horren aktibazioaz baliatuz analgesia eragin dezakete. Zoritxarrez, horietako kannabinoide batzuk psikoaktiboak dira, minaren tratamendurako mugatzailea den ezaugarria. Horregatik, azken urteotan kannabinoide ez-psikoaktiboen gaineko ikerkuntzek bultzada handia jaso dute eta minaren tratamendurako kannabinoide psikoaktibo eta ezpsikoaktiboen arteko nahasketak zenbait saio klinikotan probatu dira. Azkenik, eraginkortasun/segurtasun erlazioa hobetzeko asmoz, kannabinoide eta opiazeoen elkarketak ikertu izan dira, eragin analgesiko sinergikoa lortzeko eta dosi txikiagoak erabilita segurtasuna handitzeko. Beraz, kannabinoideen inguruko ikerkuntzak bide berriak zabaltzen ditu minaren tratamendurako estrategia farmakologiko hobeak bilatzeko.

Life sciences, 2018

The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and ... more The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electroph...

Proceedings of MOL2NET, International Conference on Multidisciplinary Sciences, 2015

BACKGROUND AND PURPOSE Regulation of μ receptor dynamics such as its trafficking is a possible me... more BACKGROUND AND PURPOSE Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opioid tolerance that contributes to inefficient recycling of opioid responses. We aimed to characterize the functional turnover of μ receptors in the noradrenergic nucleus locus coeruleus (LC). EXPERIMENTAL APPROACH We measured opioid effect by single-unit extracellular recordings of LC neurons from rat brain slices. Immunocytochemical techniques were used to evaluate μ receptor trafficking. KEY RESULTS After near-complete, irreversible μ receptor inactivation with β–funaltrexamine (β-FNA), opioid effect spontaneously recovered in a rapid and efficaciousmanner. In contrast, α2-adrenoceptor-mediated effect hardly recovered after receptor inactivation with the irreversible antagonist EEDQ. When the recovery of opioid effect was tested after various inactivating time schedules, we found that the longer the β-FNA pre-exposure, the less efficient and slower the functional ...

Basic & Clinical Pharmacology & Toxicology

Neuropharmacology, Jan 5, 2015

Nitric oxide (NO) is involved in desensitization of μ-opioid receptors (MOR). We used extracellul... more Nitric oxide (NO) is involved in desensitization of μ-opioid receptors (MOR). We used extracellular recordings in vitro to unmask the NO-dependent pathways involved in MOR desensitization in the rat locus coeruleus (LC). Perfusion with ME (3 and 10 μM) concentration-dependently reduced subsequent ME effect, indicative of MOR desensitization. ME (3 μM)-induced desensitization was enhanced by a NO donor (DEA/NO 100 μM), two soluble guanylate cyclase (sGC) activators (A 350619 30 μM and BAY 418543 1 μM) or a cGMP-dependent protein kinase (PKG) activator (8-pCPT-cGMP 30 μM). DEA/NO-induced enhancement was blocked by the sGC inhibitor NS 2028 (10 μM). A 350619 effect was also blocked by NS 2028, but not by the antioxidant Trolox. ME (10 μM)-induced desensitization was blocked by the neuronal NO synthase inhibitor 7-NI (100 μM) and restored by the PKG activator 8-Br-cGMP (100-300 μM). Paradoxically, ME (10 μM)-induced desensitization was not modified by sGC inhibitors (NS 2028 and ODQ), P...

Frontiers in Pharmacology

The pharmacological profile of cannabigerol (CBG), which acid form constitutes the main precursor... more The pharmacological profile of cannabigerol (CBG), which acid form constitutes the main precursor of the most abundant cannabinoids, has been scarcely studied. It has been reported to target α2-adrenoceptor and 5-HT1A receptor. The locus coeruleus (LC) and the dorsal raphe nucleus (DRN) are the main serotonergic (5-HT) and noradrenergic (NA) areas in the rat brain, respectively. We aimed to study the effect of CBG on the firing rate of LC NA cells and DRN 5-HT cells and on α2-adrenergic and 5-HT1A autoreceptors by electrophysiological techniques in male Sprague-Dawley rat brain slices. The effect of CBG on the novelty-suppressed feeding test (NSFT) and the elevated plus maze test (EPMT) and the involvement of the 5-HT1A receptor was also studied. CBG (30 μM, 10 min) slightly changed the firing rate of NA cells but failed to alter the inhibitory effect of NA (1–100 µM). However, in the presence of CBG the inhibitory effect of the selective α2-adrenoceptor agonist UK14304 (10 nM) was ...

Background and purpose: Previous studies have suggested a regulation of 5-hydroxytryptamine (5-HT... more Background and purpose: Previous studies have suggested a regulation of 5-hydroxytryptamine (5-HT) neurons by the endocannabinoid system. The aim of our work was to examine the effect of two CB1 receptor antagonists, SR141716A (rimonabant, Sanofi-Synthélabo Recherche, Montpellier, France) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, Tocris Cookson, Bristol, UK), on the firing rate of dorsal raphe nucleus (DRN) neurons. Experimental approach: Single-unit extracellular recordings were performed to study the effect of CB1 receptor antagonists in slices of the DRN from rat brain. Key results: Rimonabant (1 mM) and AM251 (1 mM) decreased the firing rate of about 50% of all the recorded DRN 5-HT cells. The GABAA receptor antagonist picrotoxin (20 mM) (Sigma) prevented and also reversed the inhibitory effect of rimonabant (1 mM) and AM251 (1 mM), suggesting that CB1 receptors regulate 5-HT neurons through the GABAergic system. However, the CB1/CB2 receptor agonist R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol[1,2,3-de]-1,4-benzoxazinyl]-(1naphthalenyl) methanone mesylate salt (10 mM) (WIN55212-2, Sigma, St. Louis, MO, USA) failed to change the firing activity of non-5-HT (presumably GABAergic) neurons in the DRN. The endocannabinoid N-(2-hydroxyethyl)-5Z,8Z,11Z,14Zeicosatetraenamide (anandamide, Tocris Cookson) (10 mM) also inhibited the firing activity of a number of 5-HT neurons, but this inhibition was not blocked by rimonabant (1 mM) or AM251 (1 mM), and the stable analogue R-(+) N-(2-hydroxy-1methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (methanandamide, Tocris Cookson) (10 mM) did not mimic this effect. The selective CB1 receptor agonist arachidonoyl-2-chloroethylamide (ACEA) (1 mM) only slightly increased the firing rate of DRN 5-HT cells. Conclusions and implications: These results suggest a tonic/constitutive regulation of DRN 5-HT neurons by the endocannabinoid system, which may occur through a CB1 receptor-mediated inhibition of the GABAergic system. The inhibitory effect of anandamide may be mediated through a CB1 receptor-independent mechanism.

Frontiers in Pharmacology

Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits sev... more Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects via the 5-HT1A receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT1A receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT1A autoreceptors have not been characterized. Our aim was to study the effect of CBD on the firing activity of DRN 5-HT cells and the 5-HT1A autoreceptor activation by electrophysiological and calcium imaging techniques in male Sprague–Dawley rat brain slices. Perfusion with CBD (30 μM, 10 min) did not significantly change the firing rate of DRN 5-HT cells or the inhibitory effect of 5-HT (50–100 μM, 1 min). However, in the presence of CBD (30 μM, 10 min), the inhibitory effects of 8-OH-DPAT (10 nM) and ipsapirone (100 nM) were reduced by 66% and 53%, respectively. CBD failed to reverse ipsapirone-induced inhib...

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd edition, 2017

Proceedings of MOL2NET 2017, International Conference on Multidisciplinary Sciences, 3rd edition, 2017

Introduction: Neuropathic pain is the pain that arises as a direct consequence of a lesion or dis... more Introduction: Neuropathic pain is the pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system. It could be central (postraumatic pain, multiple sclerosis, pain due to spinal cord injury, pain related to acquired immune deficiency syndrome, AIDS) or peripheral (post-herpetic neuralgia or diabetic peripheral neuropathy). Classical analgesic drugs have failed to show good efficacy for the treatment of neuropathic pain. For that reason, antiepileptic drugs such as pregabalin have been introduced for the treatment of this pain. Over the last years, pregabalin has been used to relieve neuropathic pain due to all causes leading to its over prescription. Objective: The aim of this research was to analyse the efficacy of pregabalin for the treatment of different types of neuropathic pain. Methodology: Randomized placebo controlled clinical trials were analysed following systematic methodological procedure. Results: In clinical trials that include pa...

Prostanoids are known to regulate several physiological functions and to play an important role i... more Prostanoids are known to regulate several physiological functions and to play an important role in certain pathophysiological situations such as inflammation. Prostaglandin E2 receptors (EP) are members of the G protein-coupled receptor superfamily. Four subtypes have been described: EP2 and EP4 (coupled to Gs proteins) and EP1 and EP3 (coupled to Gi/o proteins). To date, the function of the prostanoid system in the brain has not been well characterized. The locus coeruleus (LC), the main noradrenergic nucleus in the brain, has been described to express the EP3 receptor. The aim of this study was to characterize the functional relevance of EP3 receptors in the LC by single-unit extracellular recordings in rat brain slices. We performed concentration-effect curves for different endogenous derivatives and selective agonists of EP3 receptors. Thus, increasing concentrations of the EP3/EP1 agonist sulprostone (0.3-80 nM) fully inhibited the neuronal activity of LC cells, with an EC50 va...

EKAIA Euskal Herriko Unibertsitateko Zientzia eta Teknologia Aldizkaria, 2021

Loezinak, loak hartzeko edo mantentzeko zailtasunari, behar baino lehenago esnatzeari zein indarb... more Loezinak, loak hartzeko edo mantentzeko zailtasunari, behar baino lehenago esnatzeari zein indarberritzailea ez den loa edukitzeari egiten dio erreferentzia. Loezinak erritmo zirkadianoaren lo-esnatzearen alterazioak (adibidez, loaldi atzeratuaren sindromea edo lan txandekin lotutako loezina) eta ez-REM loaren esnatze asaldurak (somnanbulismoa, gaueko ikarak edo amesgaiztoak, besteak beste) barnebiltzen ditu. Loezinaren tratamendurako gehien erabiltzen diren farmakoek (bentzodiazepinek eta Z-hipnotikoek) eragin kaltegarri ugari dituzte eta epe luzera erabiltzeko ez dira gomendagarriak. Horregatik, loezina tratatzeko, ustez segurtasun hobea eta eraginkortasun bera duten alternatibak merkaturatu dira, adibidez, melatonina. Azken urteotan, melatoninaren erabilera asko handitu da eta adin guztietako pazienteengan loezin mota ugari arintzeko erabili izan da, baina ez dago argi erabilera hori ebidentzian oinarrituta dagoen. Horregatik, lan honen helburua gaixotasunekin erlaziorik ez zuen ...

Advances in Experimental Medicine and Biology, 2021

Background: Although a poor diet is the number one risk factor for early death in the United Stat... more Background: Although a poor diet is the number one risk factor for early death in the United States and globally, physicians receive little to no training in dietary interventions and lack confidence counseling patients about lifestyle modifications. Innovative, interprofessional strategies to address these gaps include the emergence of culinary medicine, a hands-on approach to teaching the role of food in health outcomes. We sought to assess the impact of a culinary medicine elective on counseling confidence, awareness of an evidence-based approach to nutrition, and understanding of the role of interprofessional teamwork in dietary lifestyle change among medical students at one undergraduate medical school. Methods: We administered pre-and post-course surveys to two cohorts of medical students (n = 64 at pre-test and n = 60 at post-test) participating in a culinary medicine enrichment elective. Chi-square analysis was used to assess the relationship between participation in the course and a positive response to each survey item. Results: Compared with the baseline, students participating in culinary medicine were more likely to feel confident discussing nutrition with patients (29% vs 92%; p < 0.001), to feel familiar with the Mediterranean diet (54% vs. 97%; p < 0.001), and to understand the role of dietitians in patient care (37% vs. 93%; p < 0.001). Conclusions: Culinary medicine shows promise as an impactful educational strategy among first-year medical students for increasing counseling confidence, promoting familiarity with evidence-based nutrition interventions, and augmenting understanding of the role of interprofessional engagement to address lifestyle-related disease.

Advances in Experimental Medicine and Biology, 2021

British journal of pharmacology, Jan 7, 2017

Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opio... more Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opioid tolerance that contributes to inefficient recycling of opioid responses. We aimed to characterize the functional turnover of μ receptors in the noradrenergic nucleus locus coeruleus (LC). We measured opioid effect by single-unit extracellular recordings of LC neurons from rat brain slices. Immunocytochemical techniques were used to evaluate μ receptor trafficking. After near-complete, irreversible μ receptor inactivation with β-funaltrexamine (β-FNA), opioid effect spontaneously recovered in a rapid and efficacious manner. In contrast, α2 -adrenoceptor-mediated effect hardly recovered after receptor inactivation with the irreversible antagonist EEDQ. When the recovery of opioid effect was tested after various inactivating time schedules, we found that the longer the β-FNA pre-exposure, the less efficient and slower the functional μ receptor turnover became. Interestingly, μ receptor t...

EKAIA Euskal Herriko Unibertsitateko Zientzi eta Teknologi Aldizkaria, 2017

Cannabis sativa landarean kannabidiola, kannabigerola edo Δ9-tetrahidrokannabibarina bezalako kan... more Cannabis sativa landarean kannabidiola, kannabigerola edo Δ9-tetrahidrokannabibarina bezalako kannabinoide ez-psikoaktiboak aurki daitezke. Oro har, kannabinoide horiek kannabinoideen hartzaileekiko (CB) afinitate txikia dutenez, ez daukate kannabinoide klasikoek (bereziki Δ9-THCak) duten aktibitate psikoaktiboa. Gizakietan eta animalietan kannabinoide ez-psikoaktiboekin egindako lehenengo ikerketek horien propietate terapeutikoak frogatu dituzte. Efektu horiek azaltzeko itu eta mekanismo desberdinak proposatu dira, besteak beste, hartzaile serotonergikoen aktibazioa edota entzima desberdinen modulazioa.

Neuroscience Letters, 2004

... Statistical evaluation was performed by one-way ANOVA followed by Dunnet's test (for com... more ... Statistical evaluation was performed by one-way ANOVA followed by Dunnet's test (for comparisons between independent groups) or by the paired Student's t-test (for comparisons within the same cells) using the computer program GraphPad Prism v. 3.00 for Windows ...

Neuropharmacology, 2012

A functional interaction between serotonergic and noradrenergic systems has been shown in the loc... more A functional interaction between serotonergic and noradrenergic systems has been shown in the locus coeruleus (LC). Noradrenaline (NA) levels in the prefrontal cortex (PFC) are dependent on the firing rate of LC neurons, which is controlled by a 2 adrenoceptors (a2ADR). The aim of the present study was to investigate the role of 5-HT 3 receptors (5HT3R) in the modulation of central noradrenergic activity. We measured extracellular NA concentrations in the LC and PFC by dual-probe microdialysis in awake rats and the firing rate of LC neurons by electrophysiological techniques in vitro. Administration of the 5HT3R agonists SR57227 (1e100 mM) and m-chlorophenylbiguanide (mCPBG, 1e100 mM) into the LC increased NA in this nucleus (E max ¼ 675 AE 121% and E max ¼ 5575 AE 1371%, respectively) and decreased NA in the PFC (E max ¼ À49 AE 6% and E max ¼ À25 AE 11%, respectively). Administration of the 5HT3R antagonist Y25130 (50 mM) into LC attenuated SR57227 effect in the LC (E max ¼ 323 AE 28%) and PFC (E max ¼ À37 AE 7%). The a2ADR antagonist RS79948 (1 mM) blocked the SR57227 effect in the PFC but it did not change the effect in the LC (E max ¼ 677 AE 202%). In electrophysiological assays, both mCPBG (1e10 mM) and SR57227 (1e10 mM) reduced the firing rate of about 50% of tested LC neurons (maximal effect ¼ À37 AE 2% and À31 AE 4%, respectively); this effect was partially blocked by Y25130 (50 mM). Administration of RS79948 (1 mM) reversed the inhibition induced by mCPBG. Competition radioligand assays against [ 3 H]UK14304 and [ 3 H]RX821002 (a2ADR selective drugs) in the rat brain cortex showed a very weak affinity of SR57227 for a2ADR, whereas the affinity of mCPBG for a2ADR was 17-fold higher than that of SR57227 for a2ADR. The present results suggest that 5HT3R stimulate NA release in the LC, which promotes simultaneously a decrease in the firing rate of LC neurons through a2ADR and then a decrease of NA release in terminal areas such as the PFC.

Osagaiz: osasun-zientzien aldizkaria, Dec 17, 2017

Ehunetako benetako kaltearekin edo kalte potentzialarekin erlazionatutako esperientzia sentsorial... more Ehunetako benetako kaltearekin edo kalte potentzialarekin erlazionatutako esperientzia sentsorial eta emozional desatsegina da mina, eta sailka daiteke jatorriaren arabera (nozizeptiboa, neuropatikoa), larritasunaren arabera (arina, larria) zein iraupenaren arabera ere (akutua, kronikoa). Oro har, gaur egun mina tratatzeko merkaturatuta dauden farmakoak eraginkorrak dira, baina epe luzera erabiltzean arazoak ager daitezke. Adibidez, opiazeoak analgesiko indartsuak diren arren, kronikoki ematean haien eraginkortasuna txikitu daiteke eta eragin desiragaitzak agertu. Estatistikak dio populazioaren % 15ek min kronikoa jasaten duela. Min kronikoak norbanakoa ezindu dezake eta hura arintzea zaila gerta daiteke. Horregatik, mina tratatzeko estrategia eta itu berrien ikerketak beharrezkoak dira. Ikergai dagoen itu bat sistema kannabinoidea da. Barneko kannabinoideak giza gorputzak ekoizten dituen molekulak dira, zeinek kannabinoide-hartzaileei (CB) lotuz funtzio fisiologiko ugari erregulatzen dituzten, mina adibidez. Cannabis generoko landareetan aurki daitezkeen landare-kannabinoideek barneko sistema horren aktibazioaz baliatuz analgesia eragin dezakete. Zoritxarrez, horietako kannabinoide batzuk psikoaktiboak dira, minaren tratamendurako mugatzailea den ezaugarria. Horregatik, azken urteotan kannabinoide ez-psikoaktiboen gaineko ikerkuntzek bultzada handia jaso dute eta minaren tratamendurako kannabinoide psikoaktibo eta ezpsikoaktiboen arteko nahasketak zenbait saio klinikotan probatu dira. Azkenik, eraginkortasun/segurtasun erlazioa hobetzeko asmoz, kannabinoide eta opiazeoen elkarketak ikertu izan dira, eragin analgesiko sinergikoa lortzeko eta dosi txikiagoak erabilita segurtasuna handitzeko. Beraz, kannabinoideen inguruko ikerkuntzak bide berriak zabaltzen ditu minaren tratamendurako estrategia farmakologiko hobeak bilatzeko.

Life sciences, 2018

The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and ... more The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electroph...

Proceedings of MOL2NET, International Conference on Multidisciplinary Sciences, 2015

BACKGROUND AND PURPOSE Regulation of μ receptor dynamics such as its trafficking is a possible me... more BACKGROUND AND PURPOSE Regulation of μ receptor dynamics such as its trafficking is a possible mechanism underlying opioid tolerance that contributes to inefficient recycling of opioid responses. We aimed to characterize the functional turnover of μ receptors in the noradrenergic nucleus locus coeruleus (LC). EXPERIMENTAL APPROACH We measured opioid effect by single-unit extracellular recordings of LC neurons from rat brain slices. Immunocytochemical techniques were used to evaluate μ receptor trafficking. KEY RESULTS After near-complete, irreversible μ receptor inactivation with β–funaltrexamine (β-FNA), opioid effect spontaneously recovered in a rapid and efficaciousmanner. In contrast, α2-adrenoceptor-mediated effect hardly recovered after receptor inactivation with the irreversible antagonist EEDQ. When the recovery of opioid effect was tested after various inactivating time schedules, we found that the longer the β-FNA pre-exposure, the less efficient and slower the functional ...

Basic & Clinical Pharmacology & Toxicology

Neuropharmacology, Jan 5, 2015

Nitric oxide (NO) is involved in desensitization of μ-opioid receptors (MOR). We used extracellul... more Nitric oxide (NO) is involved in desensitization of μ-opioid receptors (MOR). We used extracellular recordings in vitro to unmask the NO-dependent pathways involved in MOR desensitization in the rat locus coeruleus (LC). Perfusion with ME (3 and 10 μM) concentration-dependently reduced subsequent ME effect, indicative of MOR desensitization. ME (3 μM)-induced desensitization was enhanced by a NO donor (DEA/NO 100 μM), two soluble guanylate cyclase (sGC) activators (A 350619 30 μM and BAY 418543 1 μM) or a cGMP-dependent protein kinase (PKG) activator (8-pCPT-cGMP 30 μM). DEA/NO-induced enhancement was blocked by the sGC inhibitor NS 2028 (10 μM). A 350619 effect was also blocked by NS 2028, but not by the antioxidant Trolox. ME (10 μM)-induced desensitization was blocked by the neuronal NO synthase inhibitor 7-NI (100 μM) and restored by the PKG activator 8-Br-cGMP (100-300 μM). Paradoxically, ME (10 μM)-induced desensitization was not modified by sGC inhibitors (NS 2028 and ODQ), P...