pregabalin and Inflammation

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Post-burn pruritus is the pruritus that occurs after burn during the rehabilitation and healing process of burn wounds. The post-burn pruritus is a common and serious complication of burn injury, which severely lowers the quality of life of the patient. Many potential treatments are available for pruritus but there is no consensus of the best single treatment yet. The precise mechanism of post-burn pruritus has not been elucidated, but it appears to have pruritogenic and neuropathic aspects. Clinically, post-burn pruritus tends to be intractable to conventional treatment but rather responds to neuroleptic agents, such as gabapentin and pregabalin. During wound healing, various neuropeptides secreted from the nerves of the skin control epidermal and vascular proliferation and connective tissue cells. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. There are two mechanisms underlying post-burn neuropathic pruritus. The first one is peripheral sensitization. The second one is the intact nociceptor hypothesis. An effective treatment for post-burn pruritus will also be effective in other neuropathic and intractable itching. In this review, we summarized the interaction and mechanism of keratinocytes, immune cells, and nerve fibers related to post-burn pruritus.

Topics: Animals; Antipsychotic Agents; Burns; Gabapentin; Histamine Antagonists; Humans; Inflammation; Keratinocytes; Narcotic Antagonists; Neuropeptides; Ondansetron; Pregabalin; Pruritus; Receptors, Opioid; Wound Healing

Although coenzyme Q10 (CoQ10) supplementation has shown to reduce pain levels in chronic pain, the effects of CoQ10 supplementation on pain, anxiety, brain activity, mitochondrial oxidative stress, antioxidants, and inflammation in pregabalin-treated fibromyalgia (FM) patients have not clearly elucidated. We hypothesised that CoQ10 supplementation reduced pain better than pregabalin alone

Topics: Adult; Brain; Double-Blind Method; Female; Fibromyalgia; Humans; Inflammation; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Oxidative Stress; Pain; Positron-Emission Tomography; Pregabalin; Ubiquinone

Post-herpetic neuralgia (PHN) is a chronic pain that is difficult to treat and lasts a long time, which poses a threat to patients' physical and mental health (MH) and quality of life. To analyze the effectiveness of extracorporeal shock wave (ESW) combined with pregabalin on PHN and its impact on PHN patients' quality of life with the help of a random number table. Totally 164 PHN patients were assigned to a control group (n = 82) or an observation group (n = 82). The observation group was given pregabalin combined with ESW treatment, while the control group was only given pregabalin. In the 2 groups, the general clinical data of the patients were compared. The inflammation levels including erythrocyte sedimentation rate (ESR), CRP, lymphocyte count and albumin level in both groups were compared prior to and following therapy. In addition, the difference between pretreatment and post-treatment in the 2 groups was compared with respect to neuralgia and quality of life. After treatment, the observation group exhibited much lower ESR and CRP but quite higher lymphocyte count and albumin level relative to the control group (P < .05). Additionally, the improvement in visual analogue scale (VAS) scores and short form 36 (SF-36) scale scores including role-emotional (RE), MH, physical function (PF), general health (GH), bodily pain (BP), social function (SF), vitality (VT), and role-physical (RP) scores in the 2 groups were pronounced following treatment, which was more apparent in the observation group (P < .05). The combination of ESW with pregabalin can reduce the inflammation, improve the quality of life of PHN patients and effectively relieve their neuralgia.

Topics: Albumins; Analgesics; Humans; Inflammation; Neuralgia; Neuralgia, Postherpetic; Pregabalin; Quality of Life; Treatment Outcome

Transient receptor potential vanilloid 4 (TRPV4)-mediated astrocyte activation is critical to neuropathic pain. Pregabalin, a widely used drug to treat chronic pain, is reported to lower the intracellular calcium level. However, the molecular mechanism by which pregabalin decreases the intracellular calcium level remains unknown. Purinergic P2Y. Neuropathic pain was induced by chronic compression of the dorsal root ganglion (CCD) in rats. Paw withdrawal mechanical threshold (PWMT) was used for behavioral testing. Intracellular calcium concentration was measured using a fluorescent calcium indicator (Fluo-4 AM).. We found that P2Y

Topics: Animals; Antineoplastic Agents; Astrocytes; Calcium; Calcium Signaling; Inflammation; Neuralgia; Pregabalin; Rats; TRPV Cation Channels

Background Gabapentinoids are known to reduce neuropathic pain. The aim of this experimental study was to investigate whether gabapentinoids exert anti-inflammatory and/or anti-nociceptive effects at the cellular level using primary cultures of rat dorsal root ganglia (DRG). Methods Cells from rat DRG were cultured in the presence of gabapentin or pregabalin, and we tested the effects of subsequent stimulation with lipopolysaccharide (LPS) on the expression of genes (real-time polymerase chain reaction) and production of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) by specific bioassays. Using Ca2+ imaging, we further investigated in neurons the effects of gabapentinoids upon stimulation with the TRPV-1 agonist capsaicin. Results There is a small influence of gabapentinoids on the inflammatory response to LPS stimulation, namely, a significantly reduced expression of IL-6. Pregabalin and gabapentin further seem to exert a moderate inhibitory influence on capsaicin-induced Ca2+ signals in DRG neurons. Conclusions Although the single inhibitory effects of gabapentinoids on inflammatory and nociceptive responses are moderate, a combination of both effects might provide an explanation for the proposed function of these substances as an adjuvant for the reduction of neuropathic pain.

Topics: Analgesics; Animals; Capsaicin; Female; Gabapentin; Ganglia, Spinal; Inflammation; Lipopolysaccharides; Male; Neuralgia; Neurons; Pregabalin; Primary Cell Culture; Rats; Rats, Wistar; Sensory System Agents; Somatosensory Cortex

Immune system alteration has been implicated in the pathogenesis of chronic pain conditions, epilepsy and generalized anxiety disorder. Targeting cytokines has recently been proposed for the management of such conditions. Pregabalin (PGB) is an antiepileptic agent used for the management of these conditions. However, little is known about its immunomodulatory effects on cytokine secretion in vivo and in vitro. Hence, a mitogen (Lipopolysaccharide [LPS] or Concanavalin A [ConA])-induced murine model of inflammation was used to investigate the effect of PGB on in vivo and in vitro IL-1β, IL-6, TNF-α and IL-2 cytokine secretion using ELISA. In addition, PGB effect on spleen histology, as a lymphoid organ, was examined. Our results revealed that PGB significantly inhibited the secretion of ConA-induced IL-6 secretion, basal and ConA-induced TNF-α and IL-2 secretion in splenocytes in vitro. In vivo, PGB inhibited basal and LPS/ConA-induced IL-6 and TNF-α secretion in addition to LPS-induced IL-1β and ConA-induced IL-2 secretion. Moreover, PGB attenuated mitogen-induced inflammatory changes in the spleen. These findings provide an evidence of the anti-inflammatory properties of PGB on cytokine secretion and lymphoid organ inflammation. This might give insights into the role of PGB in the management of the inflammatory state in PGB-indicated conditions.

Topics: Animals; Concanavalin A; Cytokines; Disease Models, Animal; Female; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Pregabalin; Spleen

Adaptor molecule downstream of kinase-3 (DOK3) is a vital regulator of innate immune responses in macrophages and B cells, and G-protein-coupled receptor 84 (GPR84) is significant in mediating the biosynthesis and maintenance of inflammatory mediators that are induced by neuropathic pain in microglia. In the present study, we determined the role of DOK3 in activating microglia-induced neuropathic pain and investigated the underlying mechanisms associated with GPR84. We found that knockdown of DOK3 in microglial cells dramatically reduced the levels of inflammatory factors, and we uncovered a physical association between DOK3 and GPR84 in the induction of inflammatory responses. We also observed that neuropathic pain and inflammatory responses induced by chronic constriction injury (CCI) of the sciatic nerve or intrathecal injection of a GPR84 agonist were compromised in DOK3

Topics: Adaptor Proteins, Signal Transducing; Analgesics; Animals; Cell Line; Gene Knockdown Techniques; Inflammation; Mice; Mice, Knockout; Microglia; Neuralgia; Pregabalin; Receptors, G-Protein-Coupled; Sciatic Nerve

The aim of the study was to investigate the oxidative damage and inflammatory effects of sepsis on the urogenital system in the Lipopolysaccharide (LPS)-induced sepsis model and ameliorating role of Pregabalin (PGB).. Twenty-four female Wistar Albino rats (12 months old) were divided into 3 groups as follows: Sepsis group (Group S) (5 mg/kg LPS, i.p, single dose); Sepsis+ PGB group (Group SP) (5 mg/kg LPS, i.p, single dose and 30 mg/kg PGB); Control group (Group C) (0.1 ml/oral and i.p. saline, single dose), 6 h after LPS administration, the animals were killed. Subsequently, analyses of urogenital tissue oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed.. Total oxidative status (TOS) and oxidative stress index (OSI) values in the urogenital tissues were increased in Group S (Total anti-oxidative status (TAS) decreased) compared to the Control group (p < 0.05). PGB improved these values (p < 0.05). The immunohistochemical markers [Caspase-3, granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), Serum Amyloid A (SAA) and inducible nitric oxide synthase (iNOS)] were significantly increased in Group S except for bladder (p < 0.001). Statistically significant immunohistochemical positiveness was found only for IL-6 in urinary bladder, though all the others values were negative. With the administration of PGB (Group SP), the expressions of these immunoreactions were markedly decreased (p < 0.001).. These findings demonstrated that sepsis caused oxidative stress and inflammation in the urogenital tissues. We have revealed that PGB ameliorated tissue damage caused by sepsis.

Topics: Animals; Antioxidants; Biomarkers; Caspase 3; Female; Inflammation; Interleukin-6; Lipopolysaccharides; Nitric Oxide Synthase Type II; Oxidation-Reduction; Oxidative Stress; Pregabalin; Rats; Rats, Wistar; Sepsis; Urogenital System

Background L-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain. Results A seven-day treatment with L-acetylcarnitine (100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord. Conclusions Our findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain.

Topics: Acetylcarnitine; Amitriptyline; Analgesics; Animals; Chronic Disease; Disease Models, Animal; Epigenesis, Genetic; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Neuralgia; Pain Management; Pregabalin; Receptors, Metabotropic Glutamate; Time Factors; Tramadol

Topics: Aldehydes; Animals; Female; Fever; Inflammation; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Pain; Pregabalin; Saccharomyces cerevisiae

Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer's disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals' locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients. Graphical abstract Effect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Avoidance Learning; Behavior, Animal; Biomarkers; Blood Glucose; Brain; Diabetes Mellitus, Experimental; Exploratory Behavior; Inflammation; Inflammation Mediators; Male; Memory; Memory Disorders; Mice; Motor Activity; Pregabalin; Streptozocin; Time Factors

Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arthritis, Experimental; Carrageenan; Cattle; Collagen Type II; Drug Discovery; Edema; Enzyme-Linked Immunosorbent Assay; HEK293 Cells; Humans; Hydantoins; Immunoblotting; Inflammation; Interleukin-1beta; Long-Term Potentiation; Macrophages; Male; Mice, Inbred DBA; Molecular Structure; Monocytes; Neuralgia; Purinergic P2X Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X7; Structure-Activity Relationship; Sulfonic Acids; Tissue Distribution

In this study we aimed to explore the effects of pregabalin on a traumatic brain injury model in rats.. This study included 40 adult male Sprague-Dawley rats randomized into 4 groups, each of which contained equal numbers of animals. The control group had no head trauma and thus was not treated. The trauma group had head trauma but was not treated. The pregabalin group had no head trauma but was treated by pregabalin. The trauma + pregabalin group had head trauma treated with pregabalin. The biopsy samples taken from the study animals were histopathologically examined for the presence of edema, inflammation, and neuronal damage.. All animals in the trauma group had edema, inflammation, and neuronal damage. Four subjects in the control group, 6 in the pregabalin group, and 4 in the trauma + pregabalin group had edema; inflammation was present in 1 subject in the control group, 3 subjects in the pregabalin group, and 3 subjects in the trauma + pregabalin group; neuronal damage existed in 1 subject in the control group, 1 subject in the pregabalin group, and 6 subjects in the trauma+pregabalin group. The trauma group had significantly higher edema and neuronal damage scores than the other groups. Similarly, inflammation was significantly more prevalent in the trauma group than the control and trauma+pregabalin groups.. The results of the present study indicated anti-edema, anti-inflammatory, and neuroprotective effects of pregabalin in an experimental head trauma model in rats. Pregabalin may thus be beneficial in humans with acute TBI by relieving concomitant edema and inflammation.

Topics: Animals; Brain Injuries; Edema; Inflammation; Male; Pregabalin; Rats, Sprague-Dawley

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azepines; Carbolines; Chronic Disease; Constriction, Pathologic; Inflammation; Mice; Molecular Structure; Neuralgia; Pain Measurement; Rats; Spinal Nerves

The effects of maslinic acid (1), a pentacyclic triterpenoid obtained from Olea europaea, were studied in several tests for nociception in mice. Systemic administration of 1 reduced acetic acid-induced writhing, the inflammatory phase of formalin-induced pain, and capsaicin-induced mechanical allodynia. However, it did not induce motor incoordination in the rotarod test. The topical administration of 1 also reduced the inflammatory phase of the formalin test, indicating that at least some of its effects are mediated peripherally. The present results demonstrate for the first time that maslinic acid induces antinociceptive and antiallodynic effects.

Topics: Analgesics; Animals; Capsaicin; gamma-Aminobutyric Acid; Hyperalgesia; Inflammation; Mice; Molecular Structure; Olea; Pain; Pain Measurement; Pregabalin; Rotarod Performance Test; Time Factors; Triterpenes

This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST) or forced-swimming (FST) depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg), fluoxetine (20 mg/kg) and bupropion (30 mg/kg) significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg), indomethacin (10 mg/kg) and celecoxib (30 mg/kg) markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg) or pregabalin (30 mg/kg) significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg) did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg) was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg), and depression behaviour was prevented by celecoxib (30 mg/kg). The co-treatment with bupropion and celecoxib (3 mg/kg each) significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1β, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and anti-inflammatory agents bupropion and celecoxib might represent an attractive therapeutic strategy for depression.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Bupropion; Celecoxib; Cerebral Cortex; Cyclooxygenase 2; Depression; Dipyrone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Edema; Freund's Adjuvant; gamma-Aminobutyric Acid; Inflammation; Interleukin-1beta; Male; Mice; Nociception; Pregabalin; Pyrazoles; Sulfonamides

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cells, Cultured; Chronic Pain; Dogs; Humans; Hyperalgesia; Inflammation; Mice; Mice, Knockout; Microsomes, Liver; Neuralgia; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution

Our previous studies have demonstrated that application of inflammatory irritant mustard oil (MO) to the tooth pulp induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0-1.2%), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (analysis of variance (ANOVA), p<0.05). These results suggest that pregabalin may attenuate the medullary release of glutamate and associated nociceptive sensorimotor responses in this acute inflammatory pulpal pain model, and that it may prove useful for the treatment of orofacial inflammatory pain states.

Topics: Analgesics; Animals; Dental Pulp; Disease Models, Animal; Electromyography; Facial Muscles; gamma-Aminobutyric Acid; Glutamic Acid; Inflammation; Irritants; Male; Medulla Oblongata; Microdialysis; Mustard Plant; Plant Oils; Pregabalin; Rats; Rats, Sprague-Dawley; Toothache

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti-nociceptive drugs. The effect of oxycodone (0-10 mg/kg, i.p.), tramadol (0-10 mg/kg, i.p.), ibuprofen (0-300 mg/kg, i.p.) and pregabalin (0-31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan-induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti-nociceptive drugs dose-dependently reduced carrageenan-induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti-aversive versus anti-nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti-aversive and anti-nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti-aversive and anti-nociceptive potency applies to anti-nociceptive drugs with different mechanisms of action.

Topics: Analgesics; Animals; Carrageenan; Conditioning, Psychological; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Ibuprofen; Inflammation; Male; Oxycodone; Pain; Pain Measurement; Pregabalin; Rats; Rats, Sprague-Dawley; Tramadol

As one of trials on neuroprotection after spinal cord injury, we used pregabalin. After spinal cord injury (SCI) in rats using contusion model, we observed the effect of pregabalin compared to that of the control and the methylprednisolone treated rats. We observed locomotor improvement of paralyzed hindlimb and body weight changes for clinical evaluation and caspase-3, bcl-2, and p38 MAPK expressions using western blotting. On histopathological analysis, we also evaluated reactive proliferation of glial cells. We were able to observe pregabalin's effectiveness as a neuroprotector after SCI in terms of the clinical indicators and the laboratory findings. The caspase-3 and phosphorylated p38 MAPK expressions of the pregabalin group were lower than those of the control group (statistically significant with caspase-3). Bcl-2 showed no significant difference between the control group and the treated groups. On the histopathological analysis, pregabalin treatment demonstrated less proliferation of the microglia and astrocytes. With this animal study, we were able to demonstrate reproducible results of pregabalin's neuroprotection effect. Diminished production of caspase-3 and phosphorylated p38 MAPK and as well as decreased proliferation of astrocytes were seen with the administration of pregabalin. This influence on spinal cord injury might be a possible approach for achieving neuroprotection following central nervous system trauma including spinal cord injury.

Topics: Animals; Apoptosis; Astrocytes; Blotting, Western; Body Weight; Caspase 3; Cell Proliferation; Fluorescent Antibody Technique; gamma-Aminobutyric Acid; Gene Expression; Hindlimb; Inflammation; Male; Methylprednisolone; Microglia; Motor Activity; Neuroglia; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Paralysis; Pregabalin; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

Pregabalin and gabapentin are lipophilic amino acid derivatives of gamma-amino butyric acid that show anticonvulsant and analgesic activity against neuropathic pain. In this study, we investigated their actions on substance P-induced NF-kappaB activation in human neuroblastoma and rat glioma cells. Pregabalin and gabapentin decreased substance P-induced NF-kappaB activation in these cells. These drugs also inhibited NF-kappaB activation in rat spinal dorsal root ganglia cells pre-treated in vitro with substance P. These results suggest a previously undefined role of pregabalin and gabapentin in the regulation of inflammation-related intracellular signaling in both neuronal and glial cells.

Topics: Amines; Animals; Cell Line, Tumor; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Glioma; Humans; Inflammation; Neuroblastoma; NF-kappa B; Pregabalin; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance P

The over-expression of excitotoxic neurotransmitter, such as glutamate, is an important mechanism of secondary injury after spinal cord injury. The authors examined the neuroprotective effect of pregabalin (GP) which is known as to reduce glutamate secretion, in a rat model of spinal cord injury. Thirty-two male Sprague-Dawley rats were randomly allocated to four groups; the control group (contusion injury only), the methylprednisolone treated group, the minocycline treated group and the GP treated group. Spinal cord injury was produced by contusion using the New York University impactor (25 g-cm, at the 9th-10th thoracic). Functional evaluations were done using the inclined plane test and a motor rating scale. Anti-apoptotic and anti-inflammatory effects were evaluated by in situ nick-end labeling staining technique (TUNEL) and immunofluorescence staining of cord tissues obtained at 7 days post-injury. Pregabalin treated animals showed significantly better functional recovery, and anti-apoptotic and anti-inflammatory effects. Mean numbers of TUNEL positive cells in the respective groups were 63.5 +/- 7.4, 53.6 +/- 4.0, 44.2 +/- 3.9 and 36.5 +/- 3.6. Double staining (TUNEL and anti-CC1) for oligodendrocyte apoptosis, was used to calculate oligodendrocyte apoptotic indexes (AI), using the following formula AI = (No. of doubly stained cells/No. of anti-CC1 positive cells) x 100. Mean group AIs were 88.6, 46.7, 82.1 and 70.3%, respectively. Mean numbers of activated microglia (anti-OX-42 positive cells) in high power fields were 29.8 +/- 3.9, 22.7 +/- 4.1, 21.0 +/- 3.9 and 17.8 +/- 4.3, respectively. This experiment demonstrates that GP can act as a neuroprotector after SCI in rats, and its anti-apoptotic and anti-inflammatory effects are related to its neuroprotective effect. Further studies are needed to unveil the specific mechanism involved at the receptor level.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apoptosis; gamma-Aminobutyric Acid; Glutamic Acid; Inflammation; Male; Methylprednisolone; Microglia; Minocycline; Models, Animal; Pregabalin; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries

Gabapentin and pregabalin are amino acid derivatives of gamma-amino butyric acid that have anticonvulsant, analgesic, and anxiolytic-like properties in animal models. The mechanisms of these effects, however, are not well understood. To ascertain whether these drugs have effects on sensory neurons, we studied their actions on capsaicin-evoked release of the sensory neuropeptides, substance P and calcitonin gene-related peptide from rat spinal cord slices in vitro. Although release of immunoreactive peptides from non-inflamed animals was not altered by either drug, prior in vivo treatment by intraplantar injection of complete Freund's adjuvant enhanced release from spinal tissues in vitro, which was attenuated by gabapentin and pregabalin. These drugs also reduced release of immunoreactive neuropeptides in spinal tissues pretreated in vitro with the protein kinase C activator, phorbol 12,13-dibutyrate. Our results suggest that gabapentin and pregabalin modulate the release of sensory neuropeptides, but only under conditions corresponding to significant inflammation-induced sensitization of the spinal cord.

Topics: Acetates; Amines; Analgesics; Animals; Calcitonin Gene-Related Peptide; Cyclohexanecarboxylic Acids; Enzyme Activation; Foot; Freund's Adjuvant; Gabapentin; gamma-Aminobutyric Acid; In Vitro Techniques; Inflammation; Male; Phorbol 12,13-Dibutyrate; Pregabalin; Protein Kinase C; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P