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1.
Ann N Y Acad Sci ; 1255: 30-44, 2012 May.
Article in English | MEDLINE | ID: mdl-22564068

ABSTRACT

This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grünenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.


Subject(s)
Chronic Pain , Inflammation/physiopathology , Neuralgia , Pain Management/methods , Biological Products/pharmacology , Biological Products/therapeutic use , Biomedical Research , Chronic Pain/drug therapy , Chronic Pain/physiopathology , Humans , Neuralgia/drug therapy , Neuralgia/physiopathology , Translational Research, Biomedical
2.
J Pharmacol Exp Ther ; 334(2): 599-608, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20444880

ABSTRACT

The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.


Subject(s)
Analgesics/pharmacology , Hyperalgesia/physiopathology , Pain/physiopathology , Piperazines/pharmacology , Sulfones/pharmacology , gamma-Aminobutyric Acid/analogs & derivatives , Analgesics/pharmacokinetics , Animals , Calcium Channels/metabolism , Chronic Disease , Drug Interactions , Ion Channel Gating , Ligands , Male , Models, Biological , Pain Threshold/drug effects , Phosphodiesterase 5 Inhibitors , Piperazines/pharmacokinetics , Pregabalin , Purines/pharmacokinetics , Purines/pharmacology , Rats , Rats, Sprague-Dawley , Sildenafil Citrate , Sulfones/pharmacokinetics , gamma-Aminobutyric Acid/pharmacokinetics , gamma-Aminobutyric Acid/pharmacology
6.
Bioorg Med Chem Lett ; 19(1): 247-50, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19010672

ABSTRACT

A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.


Subject(s)
Amines , Cyclohexanecarboxylic Acids , Osteoarthritis/drug therapy , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Brain/metabolism , Drug Interactions , Drug Therapy, Combination , Gabapentin , Octamer Transcription Factors , Organic Anion Transporters , Oxadiazoles/pharmacology , Pregabalin , Rats
8.
Neurosci Lett ; 417(2): 187-92, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17367933

ABSTRACT

Pregabalin, a 3-substituted analogue of gamma-amino butyric acid has recently been approved for treatment of neuropathic pain. We have investigated the anatomical binding profile of [(3)H] pregabalin following chronic constriction injury (CCI) and compared this with alpha 2 delta 1 subunit expression using in situ hybridisation. We report here that the intensity and distribution pattern of [(3)H] pregabalin binding is altered in the ipsilateral dorsal horn following CCI and this is associated with a corresponding increase in alpha 2 delta 1 mRNA in the ipsilateral dorsal root ganglion (DRG). It is likely that increased DRG mRNA production leads to increased alpha 2 delta 1 protein production and subsequent transport by primary afferents to the dorsal horn. The increased expression of calcium channel subunits and protein in central terminals is interesting, given that abnormal activity within sensory nerves is likely to significantly contribute to the symptomatology of neuropathic pain. The upregulation of pregabalin binding sites in sensory nerve terminals may occur as part of the response to nerve damage in neuropathic pain patients, and therefore, preferential actions of pregabalin at these sites may contribute to its mechanism of action in man.


Subject(s)
Neuralgia/drug therapy , Nociceptors/drug effects , Peripheral Nervous System Diseases/drug therapy , Posterior Horn Cells/drug effects , gamma-Aminobutyric Acid/analogs & derivatives , Afferent Pathways/drug effects , Afferent Pathways/metabolism , Analgesics/metabolism , Analgesics/pharmacology , Animals , Binding, Competitive/drug effects , Binding, Competitive/physiology , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels/genetics , Calcium Channels, L-Type , Chronic Disease/therapy , Denervation , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ligation/adverse effects , Male , Neuralgia/metabolism , Neuralgia/physiopathology , Neurons, Afferent/drug effects , Neurons, Afferent/metabolism , Neuropeptides/antagonists & inhibitors , Neuropeptides/metabolism , Nociceptors/metabolism , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Posterior Horn Cells/metabolism , Pregabalin , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Tritium , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/pharmacology
9.
Proc Natl Acad Sci U S A ; 103(46): 17537-42, 2006 Nov 14.
Article in English | MEDLINE | ID: mdl-17088553

ABSTRACT

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (alpha2-delta-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the alpha2-delta-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.


Subject(s)
Analgesics/therapeutic use , Calcium Channels/metabolism , Pain/drug therapy , Pain/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Amino Acid Sequence , Animals , Arginine/genetics , Arginine/metabolism , Autoradiography , Base Sequence , Calcium Channels/chemistry , Calcium Channels/genetics , Calcium Channels, N-Type/metabolism , Cell Line , Chlorocebus aethiops , Constriction, Pathologic , Female , Formaldehyde , Ion Channel Gating/drug effects , Male , Mice , Mice, Transgenic , Mutation/genetics , Pain/genetics , Pregabalin , Protein Binding , Protein Subunits/chemistry , Protein Subunits/genetics , Protein Subunits/metabolism , Swine , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/therapeutic use
10.
Bioorg Med Chem Lett ; 16(9): 2333-6, 2006 May 01.
Article in English | MEDLINE | ID: mdl-15946842

ABSTRACT

A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.


Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Carboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacology , Tetrazoles/chemistry , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacology , Amines/chemistry , Animals , Anticonvulsants/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Gabapentin , In Vitro Techniques , Mice , Mice, Inbred DBA , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry
11.
J Med Chem ; 48(7): 2294-307, 2005 Apr 07.
Article in English | MEDLINE | ID: mdl-15801823

ABSTRACT

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.


Subject(s)
Amino Acid Transport System L/metabolism , Analgesics/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Anticonvulsants/chemical synthesis , Calcium Channels/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/chemical synthesis , Amines/antagonists & inhibitors , Amines/metabolism , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/antagonists & inhibitors , Cyclohexanecarboxylic Acids/metabolism , Gabapentin , In Vitro Techniques , Leucine/antagonists & inhibitors , Leucine/metabolism , Male , Mice , Mice, Inbred DBA , Pregabalin , Protein Binding , Protein Subunits/metabolism , Rats , Structure-Activity Relationship , Swine , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/pharmacology
12.
Neurosci Lett ; 370(2-3): 236-40, 2004 Nov 11.
Article in English | MEDLINE | ID: mdl-15488329

ABSTRACT

Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Sprague-Dawley rats received an intraarticular injection of either 25 microl 80 mg/ml MIA or 25 microl 0.9% sterile saline into the right knee joint. Changes in von Frey thresholds and latencies to stroking with a cotton bud (punctate and dynamic allodynia, respectively) were measured pre- and for up to 10 weeks post-intraarticular injection. Changes in hind paw weight distribution were also determined. Both punctate allodynia and a weight bearing deficit were observed in MIA-treated rats for up to 10 weeks. Interestingly, dynamic allodynia was not detected at any time point tested. Morphine (0.3-3 mg/kg, s.c.) and tramadol (3-100 mg/kg, p.o.) dose-dependently inhibited punctate allodynia and partially reversed weight bearing deficit. In conclusion, the MIA model of OA is reproducible and mimics OA pain in humans. Analgesic drug studies indicate this model may be useful for investigating chronic nociceptive pain.


Subject(s)
Disease Models, Animal , Iodoacetates , Osteoarthritis/chemically induced , Pain/physiopathology , Analysis of Variance , Animals , Chronic Disease , Enzyme Inhibitors , Functional Laterality , Hyperalgesia/physiopathology , Male , Morphine/therapeutic use , Osteoarthritis/drug therapy , Osteoarthritis/physiopathology , Pain/drug therapy , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Time Factors , Weight-Bearing/physiology
13.
J Pharmacol Exp Ther ; 303(2): 730-5, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12388658

ABSTRACT

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.


Subject(s)
Acetates/pharmacology , Amines , Benzofurans/pharmacology , Carbamates/pharmacology , Cyclohexanecarboxylic Acids , Excitatory Amino Acid Antagonists/pharmacology , Neurokinin-1 Receptor Antagonists , Pain/drug therapy , gamma-Aminobutyric Acid , Animals , Diabetes Mellitus, Experimental/physiopathology , Dose-Response Relationship, Drug , Drug Synergism , Gabapentin , Male , Pain/etiology , Pain Measurement/drug effects , Peripheral Nervous System Diseases/complications , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley
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