Twitch Response Research Articles

'Muscular wisdom' revisited: Decaying rates of stimulation mitigate torque loss.

During a sustained high-intensity isometric maximal voluntary contraction (MVC), declining motor unit firing rates (MUFRs) accompany torque loss. This decline (∼50% over 60s) helps to maintain torque by preserving peripheral electrical propagation and matching the slowing contractile properties with torque loss (i.e., 'muscular wisdom'). However, it has been suggested that reduced MUFRs contribute to torque loss. Here, we compared torque loss between constant and decaying rates of electrical stimulation to mimic MUFRs reported during MVCs. The dorsiflexors of 8 males and 5 females (21-30years) underwent three 60s muscle fatiguing conditions: (1) sustained MVC; (2) constant high-frequency electrical stimulation (40Hz); and (3) exponentially decaying stimulation rate (from 40 to 20Hz). The decaying rate demonstrated less torque loss compared with the sustained high-frequency stimulation and the MVC conditions (P<0.01). Furthermore, torque increased (by ∼17%, P<0.005) when the constant high-frequency condition was switched to 20Hz for 2s at task termination. Conversely, torque loss was accelerated when the decaying stimulation rate was switched from 20 to 40Hz for 2s at task termination (by ∼16%, P<0.001). Following all conditions, evoked twitch responses slowed (by 29%-77%, P<0.01) but M-wave amplitude was reduced only for the constant high-frequency condition (by ∼23%, P<0.01). Thus, the reduction in stimulation rates maintained optimal activation by matching the fatigue-induced contractile slowing in combination with preserved peripheral electrical conductance. Therefore, reducing the activation rate preserves torque, rather than contributing to torque loss during high-intensity contractions, thereby supporting the muscle wisdom hypothesis.

Without visual feedback voluntary torque is overestimated during muscle potentiation despite similar motor unit firing rate and perception of exertion.

The purpose was to assess whether visual feedback of torque contributes to motor unit (MU) firing rate reduction observed during post-activation potentiation (PAP) of skeletal muscle. From 15 participants 23 MUs were recorded with intramuscular fine-wire electrodes from the tibialis anterior during isometric dorsiflexion contractions at 20% of maximum, with and without both PAP and visual feedback of torque. A 5s maximal voluntary contraction (MVC) was used to induce PAP, and evoked twitch responses were assessed before and after. After the MVC twitch torque was 188% of baseline (p<0.001). Without visual feedback of torque and with participants targeting 20% MVC, torque, MU firing rates and rating of perceived exertion (RPE) were 22.8 ± 5.3 %MVC, 14.3 ± 2.6 Hz, 1.79 ± 0.93 a.u., respectively. Inducing PAP without feedback but targeting 20% MVC torque was overestimated by 50% (p<0.001) despite similar firing rates and RPE as baseline (both p≥0.3). With visual feedback, torque was not overestimated during PAP (p=0.14), however, rates and RPE were lower (13 and 20%, respectively) than baseline (both p≤0.008). Therefore, no compensatory modifications in MU output occurred despite muscle potentiation. This indicates lower voluntary drive, reflected additionally by reduced RPE, was responsible for the reduced firing rates so that torque did not exceed the required task, compared to modified peripheral feedback. During PAP, the motoneuron is not sensitive to alterations in the active state of the muscle unit per se, but rather compensatory adjustments to optimize contractile output are due to reductions in descending input.

Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice.

5-methoxy-N,N-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its N-alkyl, N-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT2A) and 1A receptors (5-HT1A), and 3) to examine the influence of 5-HT1A on 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT2A and 5-HT1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED50 range = 0.2-1.8 mg/kg) and maximal effects (Emax range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED50 range = 3.2-20.6 mg/kg). 5-HT2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT1A antagonist pretreatment enhanced HTRs. In general, N,N-dialkyl and N-isopropyl derivatives displayed HTR activity, while the N-methyl, N-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT1A unmasked latent HTR activity for the N-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT1A agonist activity can dampen 5-HT2A-mediated HTRs. Suppression of 5-HT2A-mediated HTRs by 5-HT1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT1A agonism in modulating acute psychoactive effects of 5-HT2A agonists.

Development and Testing of a Device to Detect Trigger Points, and Local Twitch Responses in Dry Needling Intervention

Trigger point dry needling (TrpDN) has emerged as a promising intervention for the treatment of myofascial pain. This involves insertion of a sterile filament needle directly into the trigger point (Trp), with the aim of eliciting a local twitch response (LTR). This sudden, involuntary contraction of the muscle fibers confirms the breakdown and success of TrpDN intervention. Not all LTRs are perceptible through visual observation or tactile sensation during the intervention. In search of noticeable LTR, clinicians perform Hong's technique (back-and-forth movements of needle in muscle). This results in muscle damage and causes pain and discomfort thereby limiting functional movements of patients. One important factor in the diagnosis and post intervention follow-up of TrpDN is the pain pressure threshold (PPT). Currently most of the clinicians use thumb pressure and subjective scales for confirming trigger points. These methods can introduce biasness due to its reliance on subjective factors.•In this present study, an effort has been made to assemble a device to overcome the challenges faced during assessment and treatment of trigger points.•This device can provide audiovisual feedback for LTR and can measure PPT.

Acute acetaminophen ingestion improves the recovery of neuromuscular fatigue following simulated soccer match-play

ObjectivesThis study aimed to investigate the impact of acute acetaminophen ingestion on the responses of neuromuscular function, biomarkers of muscle damage, and physical performance during the 72-hour recovery period following simulated soccer match-play. DesignThe study followed a crossover randomized, double-blind, placebo-controlled trial design. MethodsDuring the two experimental sessions, thirteen semi-professional male soccer players completed a 90-minute simulated soccer match, 60 min after oral ingestion of 1 g acetaminophen or placebo. Maximal voluntary contraction and twitch responses of the knee extensor muscles, elicited through electrical femoral nerve stimulation, were utilized to evaluate both peripheral fatigue (potentiated twitch force, Qtw,pot) and central fatigue (voluntary activation). Performance was assessed through countermovement jump and 20 m sprint tests. Creatine kinase and lactate dehydrogenase were also measured. ResultsSmaller reductions were observed in maximal voluntary contraction (−13.3 ± 7.5 % vs. −24.7 ± 11.1 %) and voluntary activation (−3.8 ± 4.4 % vs. −12.9 ± 5.4 %) in the acetaminophen compared to the placebo condition immediately after simulated soccer match-play (p < 0.05). Afterward, these parameters were recovered 24 h earlier in the acetaminophen session compared to the placebo session. Furthermore, the 20 m sprint performance was significantly better throughout the recovery period in the acetaminophen session compared to the placebo session. ConclusionsThe findings of this study showed that acute ingestion of 1 g of acetaminophen (1 h before exercise) attenuated the decrease in maximal voluntary contraction and voluntary activation levels after exercise, as well as improved 20 m sprint performance.

Assessing the impact of degree of fusion and muscle fibre twitch shape variation on the accuracy of motor unit discharge time identification from ultrasound images

ObjectiveUltrasound (US) images during a muscle contraction can be decoded into individual motor unit (MU) activity, i.e., trains of neural discharges from the spinal cord. However, current decoding algorithms assume a stationary mixing matrix, i.e. equal mechanical twitches at each discharge. This study aimed to investigate the accuracy of these approaches in non-ideal conditions when the mechanical twitches in response to neural discharges vary over time and are partially fused in tetanic contractions. MethodsWe performed an in silico experiment to study the decomposition accuracy for changes in simulation parameters, including the twitch waveforms, spatial territories, and motoneuron-driven activity. Then, we explored the consistency of the in silico findings with an in vivo experiment on the tibialis anterior muscle at varying contraction forces. ResultsA large population of MU spike trains across different excitatory drives, and noise levels could be identified. The identified MUs with varying twitch waveforms resulted in varying amplitudes of the estimated sources correlated with the ground truth twitch amplitudes. The identified spike trains had a wide range of firing rates, and the later recruited MUs with larger twitch amplitudes were easier to identify than those with small amplitudes. Finally, the in silico and in vivo results were consistent, and the method could identify MU spike trains in US images at least up to 40% of the maximal voluntary contraction force. ConclusionThe decoding method was accurate irrespective of the varying twitch-like shapes or the degree of twitch fusion, indicating robustness, important for neural interfacing applications.

Estimating muscle force based on a neuromuscular decoding approach adaptive to fatigue conditions

Electromyography (EMG) has been extensively employed for precise muscle force estimation. Although methods based on motor unit (MU) activities (the smallest functional unit of the neuromuscular control system) have achieved superior performance, their effectiveness in fatiguing conditions remains unknown. This study aims to investigate the performance of existing MU-based muscle force estimation methods in fatiguing conditions, including the representative neuromuscular decoding (NMD) method and firing rate (FR) −based method. Compared to FR-based method, the NMD method specifically accounts for the differences in force contributions among MUs and the force twitch response of muscle fibers. We conducted fatigue induction experiment to collect force and high-density surface EMG data from the abductor pollicis brevis muscles of eight subjects during their performance of thumb abduction. Subsequently, the analysis of myoelectric manifestation of fatigue was performed and four training–testing strategies were designed to examine the effect of fatigue on force estimation methods. Experimental results indicated that the NMD method achieved superior and stable performance (assessed through root mean square difference between estimated and actual force) across four strategies (p >0.05 revealed by ANOVA), with only slight performance decline when fatigue data was involved in training or/and testing phase. Conversely, fatigue caused significant performance degradation when using the FR-based and other five comparative methods (p <0.05). These findings demonstrate that the NMD approach is adaptive to fatiguing MU activities, which can provide precise and robust muscle force estimation against fatigue in motor control and human–machine interfaces.

Central and peripheral neuromuscular fatigue following ramp and rapid maximal voluntary isometric contractions.

Maximal voluntary isometric contractions (MVICs) as a fatiguing modality have been widely studied, but little attention has been given to the influence of the rate of torque development. Given the established differences in motor command and neuromuscular activation between ramp and rapid MIVCs, it is likely performance fatigue differs as well as the underlying physiological mechanisms. To compare responses for rapid and maximal torque following ramp and rapid MVICs, and the corresponding neuromuscular and corticospinal alterations. On separate visits, twelve healthy males (22.8 ± 2.5years) performed fatiguing intermittent MVICs of the knee extensors with either 2s (RAMP) or explosive (RAPID) ramp-ups until a 50% reduction in peak torque was achieved. Before and after each condition, maximal and rapid torque measures were determined from an MVIC. Additionally, peripheral (twitch parameters) and central (voluntary activation) fatigue, as well as rapid muscle activation, and cortical-evoked twitch and electromyographic responses were recorded. Maximal and late-phase rapid torque measures (p ≤ 0.001; = 0.635-0.904) were reduced similarly, but early rapid torque capacity (0-50ms) (p = 0.003; d = 1.11 vs. p = 0.054; d = 0.62) and rapid muscle activation (p = 0.008; d = 1.07 vs. p = 0.875; d = 0.06) decreased more after RAMP. Changes in peripheral fatigue, as indicated by singlet and doublet contractile parameters (p < 0.001 for all; = 0.752-0.859), and nerve-evoked voluntary activation (p < 0.001; 0.660) were similar between conditions. Corticospinal inhibition (via silent period) was only increased after RAPID (p = 0.007; d = 0.94 vs. p = 0.753; d = 0.09), whereas corticospinal voluntary activation and excitability were unchanged. Ramp, fatiguing MVICs impaired early rapid torque capacity more than rapid MVICs, and this was accompanied by decrements in rapid muscle activation. Responses for peripheral and central fatigue (nerve and cortical stimulation) were largely similar between conditions, except that rapid MVICs increased corticospinal inhibition.

Comparison of Postoperative Muscle Strength Recovery Between Cisatracurium and Rocuronium.

Background Neuromuscular blocking agents are crucial for anesthesia but can cause reversible paralysis, leading to risks like postoperative residual dysfunction. Undetected paralysis in thepost-anesthesia care unit (PACU) jeopardizes patient safety by impairing airway function and increasing complications. Effective reversal, assessed clinically or via nerve stimulation, is critical to prevent residual postoperative curarization (RPOC), which is linked to significant morbidity and mortality. Evaluating agents like rocuronium and cisatracurium helps optimize anesthesia outcomes and patient recovery. Methodology The study included 100American Society of Anaesthesiologists (ASA) I and II patients approved by the Institutional Review Board of Kasturba Medical College, Mangalore, India. Patients were briefed about the study, provided written informed consent, and underwent pre-anesthetic evaluations, including discussions on anesthetic procedures and associated risks. They were instructed to fast overnight after consenting. Results The study compared 100 ASA I and II patients receiving rocuronium or cisatracurium during anesthesia, analyzing age distribution (p=0.429), gender (p=0.839), ASA status (p=0.228), and physical characteristics (height, weight, BMI, p>0.05). Recovery parameters such as hand grip, sustained head lift, and double burst stimulation (DBS) twitch response showed no significant differences between groups (p=0.538 for hand grip and sustained head lift; p=0.220 for DBS. Late recovery rates at 15 minutes were observed with 16% for hand grip, 14% for sustained head lift, and 26% for DBS in the rocuronium group; compared to 14%, 10%, and 16%, respectively, in the cisatracurium group. Conclusion The study found significant postoperative residual curarization in both groups, emphasizing the need for intraoperative and PACU peripheral nerve stimulation for effective assessment. Further research on intraoperative variables could improve understanding of residual paralysis in PACU, guiding better anesthesia management.

5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.

The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear. The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM. In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice. The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10mg/kg, i.p.) in C57BL/6J mice. M100907 (50µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1mg/kg, i.p.) reduced the HTR induced by a dose of 2.5mg/kg DOM, but did not affect the response to other doses. SB242084 (1mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice. Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Correlations between the Frankfort Plane and the Presence of Myofascial Trigger Points in Posterior Cervical Musculature: An Exploratory Study.

Neck pain is a pathology with a high impact in terms of physical disability in modern society. The position of the head is related to neck pain. The Frankfort plane determines the position of the skull in space. The profile photograph of the subjects was used to determine the Frankfort plane and to study its degree of inclination. Myofascial pain syndrome is one of the most common causes of musculoskeletal pain. Trigger points are hyperirritable spots located in a palpable taut band of skeletal muscle that is painful on compression or stretch and causes a local twitch in response to snapping or palpation of the band. Objectives: The aim of this study was to analyze the relationship between the Frankfort plane and the presence of myofascial trigger points causing cervical myofascial pain. Methods: This is a cross-sectional descriptive observational study. All subjects underwent a photographic study to determine the degree of Frankfort plane inclination, and the posterior cervical musculature was palpated to find myofascial trigger points that were measured with a pressure algometer in three cervical locations on the right and left sides. Results: Our study included 47 subjects who had suffered at least one episode of cervical pain in their lifetimes. The mean age was 22.3 ± 2.9 years. Statistically significant results were found in the first right location and sports practice (p = 0.007), in the second right location and gender (p = 0.0097), in the second right location and sports practice (p = 0.0486), in the third right location and gender (p = 0.0098), and in the first, second, and third left locations and gender (p = 0.0083; p = 0.024; p = 0.0016, respectively). In the correlation between the Frankfort plane and the presence of myofascial trigger points, all locations were positive, with the first right location being statistically significant (p = 0.048). Conclusions: A positive relationship was found between the Frankfort plane and the presence of myofascial trigger points. The greater the angle of the Frankfort plane, the less the myofascial pain.

Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms.

Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT2A-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

Characteristics of patients with myofascial pain syndrome of the low back

The objective of this study is to determine characteristics of patients with myofascial pain syndrome (MPS) of the low back and the degree to which the low back pain in the patients examined can be attributed to MPS. Twenty-five subjects with myofascial trigger point(s) [MTrP(s)] on the low back participated in this cross-sectional study. The location, number, and type of selected MTrPs were identified by palpation and verified by ultrasound. Pain pressure threshold, physical function, and other self-reported outcomes were measured. Significant differences were found in Group 1 (Active), 2 (Latent), 3 (Atypical, no twitching but with spontaneous pain), and 4 (Atypical, no twitching and no spontaneous pain) of participants in the number of MTrPs, current pain, and worst pain in the past 24 h (p = .001–.01). There were interaction effects between spontaneous pain and twitching response on reports of physical function, current pain, and worst pain (p = .002–.04). Participants in Group 3 reported lower levels of physical function, and higher levels of current pain and worst pain compared to those in Group 4. Participants in Group 1 and 2 had similar levels of physical function, current pain, and worst pain. The number of MTrPs is most closely associated with the level of pain. Spontaneous pain report seems to be a decisive factor associated with poor physical function; however, twitching response is not.

Effects of psilocybin, psychedelic mushroom extract and 5-hydroxytryptophan on brain immediate early gene expression: Interaction with serotonergic receptor modulators.

Background: Immediate early genes (IEGs) are rapidly activated and initiate diverse cellular processes including neuroplasticity. We report the effect of psilocybin (PSIL), PSIL-containing psychedelic mushroom extract (PME) and 5-hydroxytryptophan (5-HTP) on expression of the IEGs, cfos, egr1, and egr2 in mouse somatosensory cortex (SSC). Methods: In our initial experiment, male C57Bl/6j mice were injected with PSIL 4.4mg/kg or 5-HTP 200mg/kg, alone or immediately preceded by serotonergic receptor modulators. IEG mRNA expression 1hour later was determined by real time qPCR. In a replication study a group of mice treated with PME was added. Results: In our initial experiment, PSIL but not 5-HTP significantly increased expression of all three IEGs. No correlation was observed between the head twitch response (HTR) induced by PSIL and its effect on the IEGs. The serotonergic receptor modulators did not significantly alter PSIL-induced IEG expression, with the exception of the 5-HT2C antagonist (RS102221), which significantly enhanced PSIL-induced egr2 expression. 5-HTP did not affect IEG expression. In our replication experiment, PSIL and PME upregulated levels of egr1 and cfos while the upregulation of egr2 was not significant. Conclusions: We have shown that PSIL and PME but not 5-HTP (at a dose sufficient to induce HTR), induced a significant increase in cfos and egr1 expression in mouse SSC. Our findings suggest that egr1 and cfos expression may be associated with psychedelic effects.

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor

Psilocybin, and its metabolite psilocin, induces psychedelic effects through activation of the 5-HT2A receptor. Psilocybin has been proposed as a treatment for depression and anxiety but sometimes induces anxiety in humans. An understanding of mechanisms underlying the anxiety response will help to better develop therapeutic prospects of psychedelics. In the current study, psilocybin induced an acute increase in anxiety in behavioral paradigms in mice. Importantly, pharmacological blocking of the 5-HT2A receptor attenuates psilocybin-induced head twitch response, a behavioral proxy for the psychedelic response, but does not rescue psilocybin's effect on anxiety-related behavior. Phosphopeptide analysis in the amygdala uncovered signal transduction pathways that are dependent or independent of the 5-HT2A receptor. Furthermore, presynaptic proteins are specifically involved in psilocybin-induced acute anxiety. These insights into how psilocybin may induce short-term anxiety are important for understanding how psilocybin may best be used in the clinical framework.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Mitigating Factors in L4 and L5 Medial Branch Motor Stimulation During Radiofrequency Ablation.

Radiofrequency ablation (RFA) is a minimally invasive procedure for facet joint pain. The targets for the procedure are the medial branches of the dorsal spinal nerves which innervate the facet joints. Before RFA, patients undergo diagnostic meal branch blocks to ensure appropriate pain relief and confirm the utility of proceeding to RFA. The success of RFA relies heavily on procedural technique and accurate placement near the medial branch. Motor testing is utilized in the lumbar region to assess the response of the multifidus and ensure proper placement of the RFA probe to prevent inadvertent damage to surrounding spinal anatomy. However, relying on motor responses in this area presents challenges given the frequency of lack of muscle twitching. Factors contributing to limited muscle twitch responses include muscle atrophy, excessive lordosis, facet arthropathy, local anesthetic use before ablation, and previous surgical neurotomy. These complexities highlight the challenges in ensuring precise motor stimulation during RFA. Despite these obstacles, accurate anatomical placement remains crucial. For RFA cases that prove challenging, relying on anatomical placement can be adequate to proceed with the procedure. Bridging knowledge gaps is vital for standardized practices and safer procedures. Further research is necessary to refine techniques, understand patient-specific factors, and enhance the efficacy of RFA in managing chronic lumbar facet joint pain.

Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties

Recent studies have sparked renewed interest in the therapeutic potential of psychedelics for treating depression and other mental health conditions. Simultaneously, the novel psychoactive substances (NPS) phenomenon, with a huge number of NPS emerging constantly, has changed remarkably the illicit drug market, being their scientific evaluation an urgent need. Thus, this study aims to elucidate the impact of amino-terminal modifications to the 5-MeO-DMT molecule on its interactions with serotonin receptors and transporters, as well as its psychoactive and thermoregulatory properties. Our findings demonstrated, using radioligand binding methodologies, that all examined 5-MeO-tryptamines exhibited selectivity for 5-HT1AR over 5-HT2AR. In fact, computational docking analyses predicted a better interaction in the 5-HT1AR binding pocket compared to 5-HT2AR. Our investigation also proved the interaction of these compounds with SERT, revealing that the molecular size of the amino group significantly influenced their affinity. Subsequent experiments involving serotonin uptake, electrophysiology, and superfusion release assays confirmed 5-MeO-pyr-T as the most potent partial 5-HT releaser tested. All tested tryptamines elicited, to some degree, the head twitch response (HTR) in mice, indicative of a potential hallucinogenic effect and mainly mediated by 5-HT2AR activation. However, 5-HT1AR was also shown to be implicated in the hallucinogenic effect, and its activation attenuated the HTR. In fact, tryptamines that produced a higher hypothermic response, mediated by 5-HT1AR, tended to exhibit a lower hallucinogenic effect, highlighting the opposite role of both 5-HT receptors. Moreover, although some 5-MeO-tryptamines elicited very low HTR, they still act as potent 5-HT2AR agonists. In summary, this research offers a comprehensive understanding of the psychopharmacological profile of various amino-substituted 5-MeO-tryptamines, keeping structural aspects in focus and accumulating valuable data in the frame of NPS. Moreover, the unique characteristics of some 5-MeO-tryptamines render them intriguing molecules as mixed-action drugs and provide insight within the search of non-hallucinogenic but 5-HT2AR ligands as therapeutical agents.