The Effects of L-NAME and Agmatine in The Nucleus Accumbens Core Regıon on Morphine Withdrawal Syndrome

Aim:The mesocorticolimbic dopaminergic system, especially the nucleus accumbens, is an important region in opioid dependence and withdrawal. Studies have shown that nitric oxide synthase inhibitors modulate the development of tolerance to opioids, opioid dependence, and withdrawal. In this study, we aimed to investigate the effects of local injections of L-NAME and agmatine into the nucleus accumbens core (NAcc), one of the nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats.Materials and Methods:Twenty-four adult Sprague-Dawley rats were used in the study. Morphine dependence was developed in all animals after guide cannula implantation into the NAcc region. On the last day of experiment, following bilateral L-NAME, agmatine or artificial cerebrospinal fluid (aCSF, control group) microinjections morphine withdrawal was induced by naloxone.Results:Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number during naloxone induced withdrawal. Local agmatine treatment significantly suppressed the score of teeth chattering, although the L-NAME did not change. No significant difference was observed in withdrawal symptoms such as wet dog shakes and defecation after local agmatine and L-NAME treatment. Agmatine increased stereotypic movements, but did not change locomotor activity behaviors such as ambulatory activity and total covered distance. Local administration of L-NAME into the NAcc did not increase stereotypic and ambulatory movements, and total covered distance during naloxone-induced withdrawal.Conclusion:These results suggest that inhibition of nitric oxide synthesis in NAcc plays a role in morphine withdrawal symptoms, but it is not responsible alone

Gamma amino-bütrik asit agonistlerinin nükleus akümbens kabuk bölgesine lokal olarak uygulanmasının naloksonla indüklenmiş morfin yoksunluğu üzerindeki etkisi

1. Opioid bağımlılığı ciddi bir sağlık sorunudur. Opioidlerin kronik kullanımı bağımlılık ve toleransa neden olur. İlaca erişim engellendiğinde/bırakıldığında yoksunluk sendromu adı verilen çeşitli fizyolojik belirtiler ortaya çıkar. Yapılan çalışmalarda nükleus akümbensin (NAc) madde bağımlılığında önemli bir merkez olduğu; GABA (Gama-Aminobütirik asit) reseptörlerinin de kötüye kullanılan ilaçların mekanizmasında modülatör rol oynadığını gösterilmiştir. Bu çalışmanın amacı naloksonla tetiklenmiş morfin yoksunluğunda, GABA agonistlerinin NAc‟ye uygulanmasının yoksunluk belirtileri üzerindeki etkisinin incelenmesidir. Çalışmada Sprague-Dawley sıçanlar kullanılmış, sıçanların NAc kabuk/çekirdek bölgesine stereotaksik cerrahi yöntemi ile bilateral klavuz kanüller yerleştirilmiştir. 75 mg baz morfin içeren 3 pelet sıçanların cilt altına hafif eter anestezisi altında 1.gün bir ve 3. gün iki adet olmak üzere implante edilmiş, 5.günde NAc‟ye enjeksiyonlar (baklofen hidroklorür (62,5, 125 ng) ya da musimol hidrobromür (50 ng)) yapılmış, ardından nalokson uygulanarak morfin yoksunluğu tetiklenmiştir. NAc kabuk bölgesine uygulanan 62,5 ng baklofenin morfin yoksunluğundaki zıplama davranışını kontrole göre istatistiksel olarak anlamlı derecede azalttığı, NAc çekirdek bölgesine uygulanan 62,5 ng baklofenin ise yoksunluk belirtilerinden zıplama, ıslak köpek titremesi ve ağırlık kaybını anlamlı derecede azalttığı saptanmıştır. NAc kabuk bölgesine uygulanan 62,5 ng baklofen morfin bağımlısı sıçanlarda lokomotor aktivite değişkenlerinden ambulatuvar, vertikal hareketlerde ve kat edilen mesafede kontrole göre anlamlı bir azalmaya neden olmuş, NAc çekirdek bölgesine uygulanan 62,5 ng baklofen ise vertikal hareketlerde istatistiksel olarak anlamlı bir azalmaya neden olmuştur. NAc kabuk bölgesine uygulanan musimol ise herhangi bir değişkende istatistiksel olarak anlamlı bir farka neden olmamıştır. Bu bulgular, NAc‟deki GABAerjik iletimin morfin yoksunluğunun çeşitli belirtileri üzerinde etkili olduğunu ve opioid bağımlılığı tedavisinde potansiyel bir mekanizma olarak araştırılması gerektiğini göstermektedir. Anahtar kelimeler: Baklofen, GABA, NAc, morfin yoksunluk sendromu, musimol 2.SUMMARY Administration of GABA agonists into nucleus accumbens shell on naloxone induced morphine withdrawal Opioid addiction is a serious public health problem. Chronic use of opioids results in tolerance to and dependence on the drug. Withdrawal syndrome is characterized by a number of physiological symptoms after the rapid cease of drugs. Studies have shown that the NAc is a crucial region in drug addiction and GABA receptors playa modulatory role in the mechanism of action of different drugs of abuse. The aim of this project is to investigate the effects of local GABA agonists in NAc during naloxone precipitated withdrawal in morphine dependent rats. Sprague-Dawley rats were stereotaxically implanted with a guide cannula to NAc shell/core and fixed to the skull.Morphine addiction was induced by subcutaneous morphine pellet (75 mg base) implantation. Three pellets were implanted on successive days, namely one on the first and two on the third day. On the fifth day local microinjections into NAc (baclofen hydrochloride (62.5, 125 ng), muscimol hydrobromide (50ng)) were administered bilaterally through guide cannulas. Baclofen microinjection into NAc shell/core (62.5 ng) significantly decreased the number of jumpings and into NAc core also significantly decreased the number of wet dog shakes and weight loss as compared to aCSF. Baclofen microinfection into NAc core/shell decreased vertical activity and into NAc shell also decreased ambulatory activity and distance as compared to aCSF. Muscimol had no effect on withdrawal symptoms. Our findings suggest that GABAergic transmission in NAc have some roles over some of the opioid withdrawal signs and should be examined as a potential mechanism that can be exploited for the treatment of opioid addiction. Keywords: Baclofen, GABA, NAc, morfin withdrawal syndrome, muscimo

Single motor unit estimation of the cutaneous silent period in ALS

OBJECTIVE: Recent evidence indicated that amyotrophic lateral sclerosis (ALS) also impairs spinal circuits, including those mediating cutaneous silent period (CSP). However, most studies utilised surface electromyography (sEMG), which needs more resolution to pinpoint changes at the single motoneuron level. We aimed to investigate CSP properties using single motor unit discharges in ALS. METHODS: In mild and severe ALS patients and controls, CSP was recorded in the first dorsal interosseus and analysed using the discharge rate method, which accurately shows the inhibitory postsynaptic potentials (IPSPs) profile. RESULTS: Our findings confirmed that the CSP latency was prolonged only in severe ALS patients. Moreover, the CSP duration was similar in each group, but late-stage ALS patients tend to have a longer CSP duration. The discharge rate method revealed a significantly longer duration (up to 150 ms) than the duration detected using sEMG. Strikingly, the motoneuron discharge rate – IPSP duration inverse relationship is lost in ALS patients, indicating a possible impairment in the motoneuron integrative properties. CONCLUSIONS: Our data support previous findings of prolonged latency, presented input–output modifications of motoneurons, and revealed the entire course of the CSP, representing a much stronger inhibitory event than previously thought. SIGNIFICANCE: Motoneuron integrative property modification assessed by CSP could be a new biomarker for ALS

Nukleus Akumbens Core Bölgesinde L-NAME ve Agmatinin Morfin Yoksunluğuna Etkileri

Aim: The mesocorticolimbic dopaminergic system, especially the nucleus accumbens, is an important region in opioid dependence and withdrawal. Studies have shown that nitric oxide synthase inhibitors modulate the development of tolerance to opioids, opioid dependence, and withdrawal. In this study, we aimed to investigate the effects of local injections of L-NAME and agmatine into the nucleus accumbens core (NAcc), one of the nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats. Materials and Methods: Twenty-four adult Sprague-Dawley rats were used in the study. Morphine dependence was developed in all animals after guide cannula implantation into the NAcc region. On the last day of experiment, following bilateral L-NAME, agmatine or artificial cerebrospinal fluid (aCSF, control group) microinjections morphine withdrawal was induced by naloxone. Results: Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number during naloxone induced withdrawal. Local agmatine treatment significantly suppressed the score of teeth chattering, although the L-NAME did not change. No significant difference was observed in withdrawal symptoms such as wet dog shakes and defecation after local agmatine and L-NAME treatment. Agmatine increased stereotypic movements, but did not change locomotor activity behaviors such as ambulatory activity and total covered distance. Local administration of L-NAME into the NAcc did not increase stereotypic and ambulatory movements, and total covered distance during naloxone-induced withdrawal. Conclusion: These results suggest that inhibition of nitric oxide synthesis in NAcc plays a role in morphine withdrawal symptoms, but it is not responsible alone.Amaç: Mezokortikolimbik dopaminerjik sistem, özellikle de nukleus akumbens bölgesi opioid bağımlılığı ve yoksunluğunda önemli bölgelerdendir. Yapılan çalışmalara göre nitrik oksit sentaz inhibitörleri opioidlere karşı tolerans gelişimini, opioid bağımlılığı ve yoksunluğunu değiştirmektedir. Biz bu çalışmada L-NAME ve agmatinin nukleus akumbens alt-bölgelerinden biri olan nukleus akumbens çekirdek (NAcc) bölgesine lokal enjeksiyonlarının morfin bağımlısı sıçanlarda naloksonla tetiklenen yoksunluk sırasında yoksunluk bulguları ve lokomotor aktivite davranışı üzerine etkilerini araştırmayı amaçladık. Materyal ve Metot: Çalışmada yirmi dört yetişkin Sprague-Dawley sıçanı kullanıldı. Tüm hayvanlarda morfin bağımlılığı NAcc bölgelerine kılavuz kanüller yerleştirildikten sonra geliştirildi. Deneyin son gününde bilateral L-NAME, agmatin veya aCSF (yapay beyin omurilik sıvısı; kontrol grubu) mikroenjeksiyonlarını takiben nalokson uygulanarak morfin yoksunluğu tetiklendi. Bulgular: NAcc bölgesine lokal uygulanan agmatin ve L-NAME morfin bağımlısı hayvanlarda nalokson sonrası sıçrama sayısını anlamlı olarak baskıladı. Lokal L-NAME tedavisi diş gıcırdatma skorunu değiştirmediği halde agmatin tedavisi anlamlı düzeyde baskıladı. Lokal L-NAME ve agmatin tedavisinden sonra ıslak köpek silkinmesi ve defekasyon gibi yoksunluk bulgularında anlamlı farklılık saptanmadı. NAcc bölgesine lokal enjekte edilen agmatin stereotipik hareketleri artırdığı halde ambulatuvar ve toplam kat edilen mesafe gibi lokomotor aktivite davranışlarında anlamlı değişiklik yapmadı. NAcc bölgesine lokal enjekte edilen L-NAME naloksonla tetiklenen yoksunluk sendromunda stereotipik hareketlerde, ambulatuvar hareketlerde ve toplam kat edilen mesafede artışa yol açmadı. Sonuç: Bu bulgular nitrik oksit üretiminin NAcc bölgesinde baskılanmasının morfin yoksunluk sendromunda rol oynadığını, fakat tek başına sorumlu olmadığını göstermektedir

Effect of aging on H-reflex response to fatigue

Ozyurt, Mustafa Gorkem/0000-0003-2531-1174; Lavender, Andrew/0000-0001-6222-880X; TURKER, KEMAL/0000-0001-9962-075XWOS: 000511788500002PubMed: 31844912Injury as a result of tripping is relatively common among older people. the risk of falling increases with fatigue and of importance is the ability to dorsiflex the foot through timely activation of the tibialis anterior (TA) muscle to ensure the foot clears the ground, or an obstacle, during the swing phase of walking. We, therefore, questioned whether the muscle spindle input to the motoneurons alters with ongoing fatigue in older people. We electrically stimulated the common peroneal nerve to assess the TA primary afferent efficacy using H-reflex before, immediately following and after a fatiguing maximal isometric contraction. M-response was kept unchanged throughout the experiment to ensure a similar stimulus intensity was delivered across time points. H-reflex increased significantly while the TA muscle was in a state of fatigue for the younger participants but tended to decrease with increasing age. the main contributor to the tonicity of TA muscle, i.e., excitatory synapses of spindle primary endings of motoneurons that innervate TA muscle, tend to lose their efficacy during fatigue in the older individuals but increased efficiency in the majority of the younger people. Since TA muscle is the main dorsiflexor of the foot and it needs to be active during the swing phase of stepping to prevent tripping, older individuals become more susceptible to falling when their muscles are fatigued. This finding may help improve devices/treatments to overcome the problem of tripping among older individuals.Turkiye Bilimsel ve Teknolojik Arastirma Kurumu [2211] Funding Source: Medlin

Transcranial magnetic stimulation induced early silent period and rebound activity re-examined.

Despite being widely studied, the underlying mechanisms of transcranial magnetic brain stimulation (TMS) induced motor evoked potential (MEP), early cortical silent period (CSP) and rebound activity are not fully understood. Our aim is to better characterize these phenomena by combining various analysis tools on firing motor units. Responses of 29 tibialis anterior (TA) and 8 abductor pollicis brevis (APB) motor units to TMS pulses were studied using discharge rate and probability-based tools to illustrate the profile of the synaptic potentials as they develop on motoneurons in 24 healthy volunteers. According to probability-based methods, TMS pulse produces a short-latency MEP which is immediately followed by CSP that terminates at rebound activity. Discharge rate analysis, however, revealed not three, but just two events with distinct time courses; a long-lasting excitatory period (71.2 ± 9.0 ms for TA and 42.1 ± 11.2 ms for APB) and a long-latency inhibitory period with duration of 57.9 ± 9.5 ms for TA and 67.3 ± 13.8 ms for APB. We propose that part of the CSP may relate to the falling phase of net excitatory postsynaptic potential induced by TMS. Rebound activity, on the other hand, may represent tendon organ inhibition induced by MEP activated soleus contraction and/or long-latency intracortical inhibition. Due to generation of field potentials when high intensity TMS is used, this study is limited to investigate the events evoked by low intensity TMS only and does not provide information about later parts of much longer CSPs induced by high intensity TMS. Adding discharge rate analysis contributes to obtain a more accurate picture about the characteristics of TMS-induced events. These results have implications for interpreting motor responses following TMS for diagnosis and overseeing recovery from various neurological conditions