Baclofen Research Articles

GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches

Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABAB receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABAB1 knockout mice; GABAB1 KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABAB1 KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABAB1 subunit of the GABAB receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABAB receptors are involved in the MOR antinociceptive effect of both male and female mice.

Relative effectiveness of N-acetylcysteine and baclofen as anticraving agents in cannabis dependence – A retrospective study with telephonic follow-up

Background:Cannabis dependence is associated with psychiatric, social, and legal consequences. Currently, there is no approved pharmacological treatment for cannabis dependence. Recent studies have reported the utility of N-acetylcysteine (NAC) and baclofen (BAC) in the long-term treatment of cannabis dependence, primarily as anticraving agents.Materials and Methods:We reviewed the records of all patients who received inpatient treatment during 2015–2017 for cannabis dependence syndrome. We included cases only if cannabis dependence was noted as the primary focus for seeking inpatient care. Data are collected up to 6 months following discharge and analyzed using Kaplan–Meier survival analysis. The time to the first use of cannabis (in days) following discharge is compared between three groups – psychosocial intervention (PSI) only, BAC in addition to PSI, and NAC in addition to PSI.Results:During the study period, 238 inpatients were diagnosed with cannabis dependence syndrome. However, cannabis dependence was the primary focus of treatment in only 72 patients. Among these patients, 29 (40.2%) received PSI only while 25 (34.8%) received BAC (mean dose = 55 mg per day, standard deviation [SD] = 2.5 mg) and 18 (25%) received NAC (mean dose = 1800 mg per day, SD = 500 mg) in addition to PSI. While 47 (62.5%) of the patients had comorbid psychiatric disorders, it was comparably distributed in the three groups. A survival analysis shows that the probability of cannabis-free survival is significantly higher in the NAC group as compared to the BAC group which is in turn higher than the PSI group (χ2 = 12.1, P = 0.002).Conclusion:The use of anticraving medications, namely BAC and NAC, may be a useful option along with PSIs in patients with cannabis dependence and requires further exploration.

Diastereomeric Salt Formation by the γ-Amino Acid RS-Baclofen and L-Malic Acid: Stabilization by Strong Heterosynthons Based on Hydrogen Bonds between RNH3+ and COOH/COO– Groups

Baclofen (BAC) is an important chiral active pharmaceutical ingredient for the treatment of specific neurological disorders that is commercially available only as RS-BAC (racemate). Using the liquid-assisted grinding technique, combination of RS-BAC with DL-MA in 1:1 stoichiometric ratio yielded a crystalline solid phase mixture of the enantiomeric salts R-BAC:L-MA and S-BAC:D-MA. Single-crystals suitable for SCXRD analysis of R-BAC:L-MA were obtained by fractional crystallization from a solution of RS-BAC and L-MA in a solvent mixture of ethyl acetate and water. Analysis of the supramolecular interaction patterns revealed that the crystal structure is stabilized by strong N+–H···–O, N+–H···O and O–H···–O hydrogen-bonding interactions. A comparative study with structurally related compounds enabled to identify common homo- and heterosynthons involving RNH3+, OH, and COOH/COO– groups. The spectroscopic, structural and thermogravimetric studies of the enantiomeric solid phase mixture of R-BAC:L-MA and S-BAC...

Baclofen overdose/withdrawal

Baclofen overdose/withdrawal

Baclofen overdose/withdrawal

Baclofen overdose/withdrawal

Baclofen abuse

Baclofen abuse

The regulatory effect of γ-aminobutyric acidB receptors in the spinal dorsal horn and dorsal root ganglion in rats with paclitaxel-induced neuropathic pain on nuclear factor-kappa B pathway

Objective To evaluate the role of γ-aminobutyric acid (GABA)B receptors in the regulation of nuclear factorr-κB (NF-κB) pathway in spinal dorsal horn and dorsal root ganglion of rats with paclitaxol-induced neuropathic pain by intrathecally using different drugs. Methods Pathogen-free male Sprague-Dawley rats (weighing 160-180 g) were used in the study. The models of rat paclitaxol-induced neuropathic pain were made by intraperitoneal injection of paclitaxel. Fourty Paclitaxol-induced neuropathic pain model rats whose paw withdrawal mechanical threshold (PWT) was equal to or less than 6 g were chosen and then randomly divided into four groups (n=10 each) according to the intrathecal administration: paclitaxel group (group P: saline 10 μl); Baclofen group (group B: baclofen 0.5 μg/10 μl); Saclofen group (group S: Saclofen 30 μg/10 μl); SN50 group (group SN: SN50 200 ng/10 μl). Ten normal rats at the same moon’s age served as the control group (group C) and then were intraperitoneally injected with constant volume solvent and intrathecally injected with 10 μl saline at the same time point. 50% PWT was measured at the point T1 (one day before intraperitoneal injection), T2 (one day before intrathecal prodrug) and T3 (120 min after intrathecal administration) respectively. The spinal dorsal horn and dorsal root ganglion (DRG) were taken out. The changes in the expression of GABAB1 receptor, NF-κBp65, interleukin (IL)-1β and tumor necrosis factor (TNF)-α was detected by molecular biological method. Results As compared with point T1, PWT in the four groups was reduced at point T2 (group P, B, A, SN P=0.001, 0.000, 0.000, 0.000). As compared with point T2, PWT in group B and group SN was increased at point T3 (group B, SN P=0.003, 0.002), while decreased in group S (P=0.007). GABAB1 receptor was down-regulated (P=0.000, 0.000) in the spinal dorsal horn (mRNA: 0.59±0.06; Western blotting: 0.42±0.05 vs. mRNA: 0.89±0.05; Western blotting: 0.66±0.02), and up-regulated in the DRG (P=0.000, 0.003) (mRNA: 1.31±0.12; Western blotting: 0.37±0.02 vs. mRNA: 0.95±0.07; /Western blotting: 0.28±0.04) in the group P as compared with the group C. Meanwhile it was found the expression of NF-κBp65 and inflammatory factors IL-1β and TNF-α in the group P was both up-regulated in the spinal horn and DRG as compared with that in group C (mRNA: P=0.000, 0.001, 0.000, 0.000, 0.000, 0.000, Western blotting: P=0.004, 0.000, 0.000, 0.000, 0.000, 0.000). As compared with the group P, the expression of GABAB1 receptor in group B was up-regulated both in the spinal horn (1.01±0.08 vs. 0.59±0.06; 0.50±0.03 vs. 0.42±0.05)and DRG (1.60±0.10 vs. 1.31±0.12; 0.50±0.03 vs. 0.37±0.02; mRNA: P=0.000, 0.000, Western blotting: P=0.004, 0.000), and the expression of NF-κBp65 and inflammatory factors IL-1β and TNF-α was both down regulated (mRNA: P=0.000, 0.000, 0.000, 0.000, 0.001, 0.000, Western blotting: P=0.000, 0.001, 0.000, 0.000, 0.000, 0.000). The recepters and factors described above had an opposite expression in the group S, and the expression of GABAB1 receptor was down-regulated (mRNA: 0.36±0.03 vs. 0.59±0.06; 0.34±0.03 vs. 1.31±0.12, Western blotting: 0.29±0.01 vs. 0.42±0.05; 0.28±0.03 vs. 0.37±0.02; mRNA: P=0.000, 0.000, 0.000, 0.000, 0.000, 0.000, Western blotting: P=0.000, 0.000, 0.000, 0.000, 0.000, 0.000) alone with the expression of NF-κBp65, IL-1β and TNF-α in the group SN (mRNA: P=0.000, 0.000, Western blotting: P=0.000, 0.003). Conclusion The expression of NF-κB and inflammatory factors IL-1β and TNF-α in the spinal dorsal horn and DRG of rats with paclitaxel-induce neuropathic pain decreased when activating the GABAB receptor or blocking the NF-κB in the spinal dorsal, resulting in the release of pain, in which NF-κB plays a key role. Key words: Paclitaxel; Neuropathic pain; γ-aminobutyric acid B1 receptor; Nuclear factorr-κ B pathway

Weakness and numbness of extremities with bowel and bladder dysfunction for four years

Weakness and numbness of extremities with bowel and bladder dysfunction for four years

Validated Method for the Screening and Quantification of Baclofen, Gabapentin and Pregabalin in Human Post-Mortem Whole Blood Using Protein Precipitation and Liquid Chromatography-Tandem Mass Spectrometry.

There has been a rapid increase in the number of prescriptions for baclofen (BLF), gabapentin (GBP) and pregabalin (PGL) in the UK since their introduction to therapy. Recent studies across the European Union and USA have shown the illicit abuse potential of these drugs and deaths have been observed. A simple, reliable and fully validated method was developed for the screening and quantification of BLF, GBP and PGL in human post-mortem (PM) blood. The analytes and their deuterated analogs as internal standard were extracted from blood using a single addition acetonitrile protein precipitation reaction followed by analysis using liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous confirmation and quantification. The assay was linear from 0.05 to 1.00 µg/mL for BLF and 0.5 to 50.0 µg/mL for GBP and PGL, respectively with r2 > 0.999 (n = 9) for all analytes. Intra-day and inter-day imprecisions (n = 80) were calculated using one-way ANOVA; no significant difference (P > 0.99) was observed for all analytes over 8 non-consecutive days. The average recovery for all analytes was >98.9%. The limits of detection and quantification were both 0.05 µg/mL for BLF, and 0.5 µg/mL for GBP and PGL. The method was highly selective with no interference from endogenous compounds or from 54 drugs commonly encountered in PM toxicology. To prove method applicability, 17 PM blood samples submitted for analysis were successfully analyzed. The concentration range observed in PM blood for BLF was 0.08-102.00 µg/mL (median = 0.25 µg/mL), for GBP 1.0-134.0 µg/mL (median = 49.0 µg/mL) and 2.0-540.0 µg/mL (median = 42.0 µg/mL) for PGL.

Clinical observation of acupuncture combined with acupoint injection in the treatment of post-stroke intractable hiccup

Objective To observe the clinical therapeutic effect of acupuncture combined with acupoint injection in the treatment of post-stroke intractable hiccup. Methods 120 patients with post-stroke intractable hiccup were randomly divided into treatment group(60 cases) and control groups(60 cases) according to the digital table.The patients in the control group were treated with baclofen tablets and methloxetamine hydrochloride injection, and the patients in the treatment group were treated with acupuncture combined with acupoint injection therapy.The treating period was 1 week.The scores of hiccup symptoms, the total effective rate and side effect were recorded before and after the treatment in all patients. Results The scores of hiccup symptoms before treatment in the treatment group and the control group were (5.32±1.17)points and (5.25±0.65)points respectively, there was no statistically significant difference between the two groups(t=1.79, P=0.96). The scores of hiccup symptoms on the 1 day after treatment in the treatment group and the control group were (3.97±1.24)points and (3.85±1.02)points respectively, there was no statistically significant difference between the two groups(t=1.93, P=0.48). The scores of hiccup symptoms on the 3 days after treatment in the treatment group and the control group were (2.80±0.73)points and (3.75±1.11)points respectively, there was significant difference between the two groups(t=2.66, P=0.00), that in the treatment group was lower than the control group.The scores of hiccup symptoms on the 5 days after treatment in the treatment group and the control group were (2.25±1.07)points and (3.43±0.81)points respectively, there was significant difference between the two groups(t=2.85, P=0.00), that in the treatment group was lower than the control group.The scores of hiccup symptoms on the 7 days after treatment in the treatment group and the control group were (1.27±0.66)points and (2.02±0.98)points respectively, there was significant difference between the two groups(t=1.07, P=0.00), that in the treatment group was lower than the control group.The total effective rates in the treatment group and the control group were 90%(54/60) and 65%(39/60) respectively, there was significant difference between the two groups(χ2=10.75, P=0.00). The incidence rates of side effects in the treatment group and the control group were 1.7%(1/60) and 6.7%(4/60) respectively, there was no statistically significant difference between the two groups(χ2=0.84, P=0.36). Conclusion Acupuncture combined with acupoint injection can significantly reduce the hiccup symptom score of post-stroke intractable hiccup patients on the 3, 5 and 7 days after treatment, and improve the total effective rate. Key words: Acupuncture and acupuncture point inject; Post-stroke intractable hiccup; Clinical observation

Comparison of the effects of Baimai ointment and baclofen in stroke patients with spasticity

Objective To compare the effects of Baimai ointment and baclofen in stroke patients with spasticity. Methods 84 cases accompanied by limb spasticity in stroke patients by digital table were randomly divided into Baimai ointment group and baclofen group, 42 cases in each group.The Baimai ointment group were treated with Baimai ointment on the spastic limbs, the baclofen group received oral baclofen tablets 30-75mg/days for 2 weeks, 4 weeks, 8 weeks.The curative effects of the two groups were compared before and after treatment. Results Before and after treatment in the two groups, the levels of spasticity, pain and activities of daily living (ADL) differences were statistically significant and Baimai ointment in the treatment of spasm.After 4 weeks and 8 weeks, the Ashworth score of the Baimai ointment group were (1.59±0.46)points, (0.89±0.56)points, and those of baclofen group were (1.75±0.64)points, (1.45±0.48)points, the differences were statistically significant(t values were 2.916, 3.367, all P<0.05). After 2 weeks, 4 weeks and 8 weeks, the VAS score of the Baimai ointment group were (2.72±0.54)points, (2.02±0.24)points, (1.24±0.12)points, and baclofen group were (3.56±0.44)points, (3.15±0.48)points, (2.58±0.26)points, the differences were statistically significant(t values were 2.975, 3.359, 5.416, all P<0.05), activities of daily living (ADL) was higher than that of the baclofen group.After 8 weeks, the MBI score of the Baimai ointment group was (64.46±10.78)points, and baclofen group was (50.74±9.18)points, the difference was statistically significant between the two groups (t values was 3.562, P<0.05). Conclusion Baimai ointment has the better antispasmodic effect than baclofen in patients with stroke. Key words: Baimai ointment; Baclofen; Stroke; Spasticity

Baclofen overdose/withdrawal

Baclofen overdose/withdrawal

Does baclofen have antidepressant qualities?

Does baclofen have antidepressant qualities?

(360) Baclofen and opioid synergism in mice

(360) Baclofen and opioid synergism in mice

Baclofen differentially mediates fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats

Rats display both fructose-conditioned flavor preference (CFP) and quinine conditioned flavor avoidance (CFA). Dopamine (D1 and D2), muscarinic and nicotinic, but not NMDA or opioid receptor antagonists reduced fructose-CFP expression. Dopamine D1, dopamine D2, muscarinic or NMDA, but not opioid or nicotinic receptor antagonists reduced fructose-CFP acquisition. Dopamine D1, NMDA, nicotinic or opioid, but not dopamine D2 or muscarinic receptor antagonists enhanced quinine-CFA acquisition. Baclofen (BAC), a GABAB receptor agonist, alternately enhances or reduces feeding under specific conditions. The present study examined whether systemic BAC administration mediated fructose-CFP expression and acquisition or quinine-CFA acquisition. Fructose-CFP expression studies trained rats with one flavor (CS+) in 8% fructose and 0.2% saccharin and a second (CS−) flavor in 0.2% saccharin, followed by vehicle (VEH) and BAC (0.5–5mg/kg) preceding 2-bottle (CS+, CS−) 0.2% saccharin choice tests. Fructose-CFP acquisition studies administered VEH or BAC (3 or 5mg/kg) prior to CS+ and CS− training sessions followed by six 2-bottle (CS+, CS−) 0.2% saccharin choice tests. Quinine-CFA acquisition studies administered VEH or BAC (3 or 5mg/kg) prior to CS− (8% fructose+0.2% saccharin) and CS+ (fructose+saccharin+0.030% quinine) training sessions followed by six 2-bottle (CS−, CS+) fructose+saccharin choice tests. BAC (3mg/kg) minimally (66%) reduced fructose-CFP expression. BAC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was enhanced by the 5mg/kg BAC dose (15–25%) relative to VEH (34–48%). These data implicate GABAB receptor signaling in acquisition of quinine avoidance with minimal or no effects upon fructose preferences.

Formulation and Evaluation of Baclofen Floating Tablets

Formulation and Evaluation of Baclofen Floating Tablets

Simultaneous determination of paracetamol, caffeine and codeine in tablets and human plasma by micellar liquid chromatography

A simple, rapid, sensitive and eco-friendly liquid chromatographic method was developed and validated for the simultaneous determination of paracetamol (PAR), caffeine (CAF) and codeine (COD). The separation was performed on cyano column using a micellar mobile phase consists of 140 mM sodium dodecyl sulfate, 25 mM phosphate buffer and 10% acetonitrile at pH = 3. The analysis was performed at a flow rate of 1 mL/min and a column temperature of 30 °C under direct UV detection at 210 nm. Total analysis time was below 6 min. Baclofen (BCF) was used as an internal standard. The validation was performed according to the ICH guidelines. The proposed method was linear over the ranges of 0.2-100.0, 0.02-12.0 and 0.2-12.0 µg/mL for PAR, CAF and COD, respectively. The limits of detection were 0.031, 0.007 and 0.054 µg/mL and limits of quantification 0.103, 0.02 and 0.164 µg/mL for PAR, CAF and COD, respectively. The results show that the procedure is suitable for the routine analysis of drugs in tablet dosage forms. The method was further extended to the determination of the studied drugs in spiked human plasma with mean percentage recoveries of 99.61±0.530, 99.28±0.523 and 99.52±0.385 for PAR, CAF and COD, respectively.

Effect of Gabapentin and Baclofen on Histology Study in Neuropathic Pain

Neuropathic pain resulted from injury to nerves is often resistant to current treatments and can seriously cause chronic pain if no appropriate treatment is given. This study was designed to prove the effectiveness of gabapentin and baclofen in increasing latency time toward thermal stimulus and recovering the morphology of dorsal horn of spinal cord in neuropathic-induced chronic pain. Forty mice were divided into 8 groups i.e sham, negative control, gabapentin at three different doses (10, 30, 100 nmol) and baclofen at three different doses (1, 10, 30 nmol). Neuropathic condition was induced by ligation of sciatic nerve with Partial Sciatic Nerve Ligation (PSNL) method. Gabapentin and baclofen were administrated intrathecally once a day for seven days, a week after neuropathic induction. Latency time toward thermal stimulus was measured on days 0, 1, 3, 5, 7, 8, 10, 12 and 14 after induction. Histology of the dorsal horn of spinal cord tissue was examined by haematoxylline-eosin staining. The results showed that intrathecal injection of gabapentin and baclofen significantly increased latency time of mice toward thermal stimulus compared with negative control. Gabapentin and baclofen are effective as treatment for neuropathic pain. They can also help the recovery process of the histology in dorsal horn in neuropathic pain. Keywords: Baclofen, dorsal horn, gabapentin, neuropathic pain, PSNL Efek Gabapentin dan Baclofen terhadap Studi Histologi pada Nyeri Neuropati Nyeri neuropati berasal dari luka pada saraf yang umumnya sulit diterapi sehingga menyebabkan nyeri kronik bila tanpa managemen terapi yang tepat. Tujuan penelitian ini adalah membuktikan efektivitas gabapentin dan baclofen dalam meningkatkan waktu ketahanan terhadap panas dan memperbaiki morfologi dorsal horn dari spinal cord pada keadaan nyeri kronik yang disebabkan neuropati. Empat puluh mencit terbagi ke dalam delapan kelompok, yaitu sham, kontrol negatif, gabapentin (dosis 10, 30 dan 100 nmol) serta baclofen (dosis 1, 10 dan 30 nmol). Nyeri neuropati diinduksi menggunakan metode Partial Sciatic Nerve Ligation (PSNL). Gabapentin dan baclofen diberikan secara intratekal satu kali sehari selama tujuh hari pada satu minggu setelah induksi nyeri neuropati. Waktu ketahanan terhadap stimulus panas diamati pada hari ke-0, 1, 3, 5, 7, 8, 10, 12, dan 14 setelah induksi. Histologi dorsal horn dari spinal cord mencit diamati menggunakan pewarnaan haematoxylline-eosin. Injeksi intratekal gabapentin dan baclofen meningkatkan waktu ketahanan terhadap stimulus panas secara signifikan dibandingkan kontrol negatif. Gabapentin dan baclofen efektif sebagai terapi nyeri neuropati. Keduanya juga dapat memperbaiki histologi dorsal horn pada kondisi nyeri neuropati. Kata kunci: Baclofen, dorsal horn, gabapentin, nyeri neuropati, PSNL

Synthesis of (R)-Baclofen

Key words (R)-baclofen - asymmetric synthesis - Michael addition - organocatalysis - thioureas - nitroalkanes - enones - γ-nitro ketones

The GIRK2 subunit is involved in IS-like seizures induced by GABA(B) receptor agonists.

Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABA(B)R-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABA(B)R agonists. GIRK2(-/-), (+/-), and (+/+) mice were treated with γ-butyrolactone (GBL), a pro-drug of the GABA(B)R agonist γ-hydroxybutyric acid, and the specific GABA(B)R agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose-response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms. Analysis of EEG and behavior of GIRK2(-/-), (+/-), and (+/+) mice after treatment with GABA(B)R agonists and antagonists, indicate that GIRK2(-/-) mice are highly resistant to GABA(B)R agonist-induced EEG and behavioral changes. These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.