Antiallodynic effects of intrathecal tianeptine in a neuropathic pain rat

BACKGROUND: Tianeptine is an antidepressant drug which is used for treating depression. Interestingly, the tianeptine has shown antinociceptive effects within a variety of nociceptions. The aim of this study is to investigate the antiallodynic effects of tianeptine in neuropathic pain rats and also determine the involvements of serotonergic, alpha-2 adrenergic and adenosine receptors at the spinal level. METHODS: Neuropathic pain was induced by ligation of left lumbar at 5th and 6th spinal nerves in male Sprague-Dawley rats. PE-10 catheters were placed into the thoracolumbar subarachnoid space for drug injections. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament when applying on the plantar surface of rats. The effects of intrathecal tianeptine were observed at 15, 30, 60, 90, 120, 150, 180 minutes after delivery. Antagonists for serotonergic (dihydroergocristine), alpha-2 adrenergic (yohimbine) and adenosine (CGS 15943) receptors were intrathecally administered 10 minutes prior to tianeptine in order to evaluate the involvement of both receptors. RESULTS: Intrathecal tianeptine increased dose-dependently at the withdrawal threshold in the ligated paw. Pretreatment with intrathecal dihydroergocristine, yohimbine and CGS 15943 antagonized the antiallodynic effects of tianeptine. CONCLUSIONS: These results suggested that intrathecal tianeptine attenuates the spinal nerve ligation induced tactile allodynia. Serotonergic, alpha-2 adrenergic and adenosine receptors are all involved in the antiallodynic effects of tianeptine at the spinal level.

Association between Single Nucleotide Polymorphisms of alpha2A-, alpha2B-, and alpha2C-Adrenergic Receptor Genes and Risk of Cerebral White Matter Lesion / 대한뇌졸중학회지

BACKGROUND: An alpha2-adrenergic receptor (alpha2-AR, ADRA2) mediates induction of hypotension and inhibition of lipolysis and insulin secretion. We evaluated whether single nucleotide polymorphisms (SNPs) of alpha2A (ADRA2A), alpha2B (ADRA2B), and alpha2C (ADRA2C) adrenergic receptors are associated with cerebral white matter lesion (cWML). METHODS: Total 336 study subjects who had no stroke were enrolled in this study. The Indices of cWML include total WML (TWML), periventricular WML (PVWML), and subcortical WML (SCWML) on brain fluid-attenuated inversion recovery (FLAIR) image. Common genetic variants of ADRA2A (1780G>A), ADRA2B (Ins/Del301-303), and ADRA2C (Ins/Del322-325) were examined. RESULTS: Among 336 study subjects, cWML was found in 66 patients (20%). In multivariate analysis, there were no significant effects of all tested ADRA2 polymorphisms on TWML. Significant association of ADRA2A 1780 AA genotype was found in PVWML (OR: 3.368, 95% CIs: 1.280-8.865, adjusted p-value after false discovery rate (FDR) correction=0.014) but not SCWML. CONCLUSION: Although SNPs of three ADRA2 subtypes failed to reach a significance in overall risk for cWML, the ADRA2A 1780G>A polymorphism may be associated with development of PVWML.

The Antiallodynic Effect and the Change of the alpha2 Adrenergic Receptor Subtype mRNA Expression by Morphine Administration in a Spinal Nerve Ligation Rat Model

BACKGROUND: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the alpha2 adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. METHODS: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 mg/kg, 3 mg/kg, 5 mg/kg) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 mg/kg) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the alpha2 subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). RESULTS: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the alpha2A, alpha2B, alpha2C subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. CONCLUSIONS: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of alpha2 receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the alpha2 subtype gene expression.

The Expression of alpha2-Adrenergic Receptor Subtypes in the Central Nervous System of Peripheral Nerve Injured Rats / 대한마취과학회지

BACKGROUND: The change of expression of the alpha2-adrenergic receptor (alpha(2)-AR) subtypes in the thalamus and hypothalamus were investigated in a neuropathic pain rat model. METHODS: The left sciatic nerve was clamped for creating a neuropathic pain model in five rats. A sham operation was done in three rats as control group. Behavioral tests for pain were conducted by using mechanical stimuli applied to the hind paws. After 7 days, the expression of alpha(2)-AR subtype mRNA in the rat thalamus and hypothalamus was measured using real time polymerase chain reaction. RESULTS: Mechanical allodynia were developed on postoperative 1, 3, and 7 days in the neuropathic pain model. The expression of alpha(2A)-AR, alpha(2B)-AR, and alpha(2C)-AR was significantly higher in the thalamus and hypothalamus in the neuropathic pain model (P > 0.05). CONCLUSIONS: These results would suggest that the subtypes of alpha(2)-AR in thalamus and hypothalamus may contribute to produce neuropathic pain.

G-protein Effects on 3HRX821002 Binding to Alpha-2 Adrenoceptor in Rat Brain / 대한정신약물학회지

OBJECTIVE: This study is to explore the effects on specific bindings between [ 3H]RX821002, alpha-2 adrenergic receptor antagonist and alpha-2 adrenergic receptor in rat brain by G-protein modulation. METHODS: The radioligand binding receptor study was conducted with [ 3H]RX821002, a new alpha-2 adrenergic receptor antagonist, in the presence or absence of Gpp(NH)p and pertussis toxin. RESULTS: The alpha-2 adrenergic receptors were saturated with [ 3H]RX821002 in the fashion of the single binding site. The dissociation constant (Kd) was 0.70+/-0.30 nM, and maximum binding (Bmax) was 599.9+/-283.4 fmol/mg protein. The saturation study showed that the maximum binding (B max ; 668.0+/-50.1 fmol/mg protein) was increased and the dissociation constant (Kd ; 0.61+/-0.14 nM) was decreased significantly in the presence of Gpp (NH)p compared to those (B max ; 559.8+/-81.9 fmol/mg protein, Kd ; 0.87+/-0.14 nM) in the absence of Gpp (NH)p (by paired t-test ; B max, p=0.023, Kd, p=0.005). In the presence of pertussis toxin, the maximum binding (B max ; 617.0+/-58.5 fmol/mg protein) was increased significantly (by paired t-test ; B max, p=0.001) but the issociation constant (Kd ; 0.92+/-0.24 nM) was not decreased compared to those (B max ; 554.1+/-66.1 fmol/mg protein, Kd ; 0.89+/-0.24 nM) in the absence of pertussis toxin. CONCLUSION: These results confirm that the binding profiles between [ 3H]RX821002 and alpha-2 adrenergic receptors be modified by G-protein modulation. This suggests that the drug effects on receptors be influenced by various conditions such as G-protein modulation.

Changes in the alpha2-Adrenergic Receptor Subtypes Gene Expression in Rat Dorsal Root Ganglion and Spinal Cord in an Experimental Model of Neuropathic Pain / 대한해부학회지

While the pathophysiological mechanism by which sympathetic nervous system generates neuropathic pain is not clear, it is thought to involve an alpha-adrenergic receptor (AR). In the present experiment, we have elucidated the distribution of alpha2-AR subtypes mRNA in the DRG and spinal cord of normal rat with in situ hybridization (ISH) and analyzed changes in their expression in an experimental model of neuropathic pain with reverse transcriptase-polymerase chain reaction (RT-PCR). The results obtained were as follows; 1. The majority of small, medium and large DRG neurons of non-operated rats expressed alpha2C-AR mRNA. alpha2A-AR-expressing neurons were primarily medium-sized and large, comprising about 16% of the total neurons present. alpha2B-AR-expressing neurons were not identified. In the spinal cord, alpha2A-AR mRNA were localized in neurons of lamina II and III, and large motor neurons in the ventral horn. alpha2C-AR mRNA was found in large motor neurons. 2. In the ligated animals, RT-PCR results showed that alpha2A-AR mRNA levels in L5, 6 DRGs on the ipsilateral side significantly increased compared to those of the contralateral sides and also to those of sham-operated rats. alpha2C-AR mRNA levels showed a marked decrease in ipsilateral L5, 6 DRGs. In the spinal cord, there was no detectable changes in alpha2A- and alpha2C-AR mRNAs levels. The present results indicate that alpha2A- and alpha2C-ARs in the DRG may play an important role in generating sympathetically maintained neuropathic pain and that alpha2-AR in the spinal cord seems not to be involved.