ABSTRACT
A novel class of potent NaV1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse NaV1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high NaV1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e. Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse NaV1.7 with high selectivity over NaV1.1, NaV1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.
ABSTRACT
Neuropathic pain, an intractable pain symptom that occurs after nerve damage, is caused by the aberrant excitability of spinal dorsal horn (SDH) neurons. Gabapentinoids, the most commonly used drugs for neuropathic pain, inhibit spinal calcium-mediated neurotransmitter release by binding to α2δ-1, a subunit of voltage-gated calcium channels, and alleviate neuropathic pain. However, the exact contribution of α2δ-1 expressed in SDH neurons to the altered synaptic transmission and mechanical hypersensitivity following nerve injury is not fully understood. In this study, we investigated which types of SDH neurons express α2δ-1 and how α2δ-1 in SDH neurons contributes to the mechanical hypersensitivity and altered spinal synaptic transmission after nerve injury. Using in situ hybridization technique, we found that Cacna2d1, mRNA coding α2δ-1, was mainly colocalized with Slc17a6, an excitatory neuronal marker, but not with Slc32a1, an inhibitory neuronal marker in the SDH. To investigate the role of α2δ-1 in SDH neurons, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system and showed that SDH neuron-specific ablation of Cacna2d1 alleviated mechanical hypersensitivity following nerve injury. We further found that excitatory post-synaptic responses evoked by electrical stimulation applied to the SDH were significantly enhanced after nerve injury, and that these enhanced responses were significantly decreased by application of mirogabalin, a potent α2δ-1 inhibitor, and by SDH neuron-specific ablation of Cacna2d1. These results suggest that α2δ-1 expressed in SDH excitatory neurons facilitates spinal nociceptive synaptic transmission and contributes to the development of mechanical hypersensitivity after nerve injury.
ABSTRACT
Gabapentinoids are specific ligands for the α2δ-1 subunit of voltage-gated calcium channels. This class of drugs, including gabapentin and pregabalin, exert various pharmacological effects and are widely used for the treatment of epilepsy, anxiety, and chronic pain. The mechanism of action of gabapentinoids involves both direct modulation of calcium channel kinetics and inhibition of channel trafficking and expression, which contribute to the above pharmacological effects. In the present study, we investigated the effects of mirogabalin, a novel potent gabapentinoid, on expression levels of the α2δ-1 subunit in the spinal dorsal horn in a rat model of spinal nerve ligation (SNL) as an experimental animal model for peripheral neuropathic pain. The neuropathic pain state was induced by SNL in male Sprague - Dawley rats. After the development of mechanical hypersensitivity, the animals received 10 mg/kg mirogabalin or vehicle orally for 5 consecutive days and were subjected to immunohistochemical analysis of α2δ-1 subunit expression in the spinal cord. In the SNL model rats, expression of the α2δ-1 subunit significantly increased in the spinal dorsal horn at the ipsilateral side of nerve injury, while mirogabalin inhibited this increase. In conclusion, the α2δ-1 subunit was upregulated in the spinal dorsal horn of SNL model rats, and repeated administration of mirogabalin inhibited this upregulation. The inhibitory effect of mirogabalin on upregulation of the α2δ-1 subunit after nerve injury is considered to contribute to its analgesic effects in peripheral neuropathic pain.
Subject(s)
Calcium Channels, L-Type , Neuralgia , Rats , Male , Animals , Up-Regulation , Calcium Channels, L-Type/metabolism , Calcium Channels, L-Type/therapeutic use , Rats, Sprague-Dawley , Neuralgia/drug therapy , Neuralgia/metabolism , Spinal Nerves/metabolism , Spinal Cord Dorsal Horn/metabolismABSTRACT
We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound. The scaffold was inspired by fentanyl or pethidine, which possess potent analgesic activities. DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR). The mechanism of analgesic action of DS21980956 was considered to differ from a biased ligand, for example, TRV-130 (3, oliceridine).
Subject(s)
Amines/therapeutic use , Analgesics/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Pain/drug therapy , Acetic Acid , Amines/chemistry , Analgesics/chemistry , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Dose-Response Relationship, Drug , Mice , Mice, Inbred Strains , Molecular Structure , Pain/chemically induced , Pain Measurement , Structure-Activity RelationshipABSTRACT
We identified (5'S)-10'-fluoro-6'-methyl-5',6'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,6]diaza[2,5]methano[2,6]benzodiazonin]-7'(1'H)-one, 22b (DS34942424) with a unique and original bicyclic skeleton. 22b showed an orally potent analgesic in the acetic acid-induced writhing test and formalin test in ddY mice without sedation. Moreover, 22b did not exhibit mu opioid receptor agonist activity.
Subject(s)
Analgesics, Opioid/chemistry , Receptors, Opioid, mu/agonists , Spiro Compounds/chemistry , Administration, Oral , Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Stability , Male , Mice , Microsomes, Liver/metabolism , Pain/chemically induced , Pain/drug therapy , Pain/pathology , Receptors, Opioid, mu/metabolism , Spiro Compounds/metabolism , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV)1.7 inhibitors is described. By the modification of amide or urethane bond in NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 µM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED50: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Neuralgia/drug therapy , Voltage-Gated Sodium Channel Blockers/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Male , Mice , Molecular Structure , Neuralgia/metabolism , Structure-Activity Relationship , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/chemistryABSTRACT
A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
Subject(s)
Analgesics/therapeutic use , Hyperalgesia/drug therapy , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/therapeutic use , Analgesics/chemical synthesis , Analgesics/toxicity , Animals , Drug Discovery , Female , Humans , Macaca fascicularis , Male , Mice , Microsomes, Liver/metabolism , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/toxicity , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/toxicityABSTRACT
BACKGROUND: Mental disorders including anxiety and depression are common comorbidities in fibromyalgia patients, and exert a profound impact on their quality of life. Mirogabalin, a novel ligand for the α2δ-subunit of voltage-gated calcium channels, shows analgesic effects in fibromyalgia and neuropathic pain models. To provide additional information regarding its potential utility for treating chronic pain, we examined its anxiolytic-like effects in rats repeatedly injected with acidic saline intramuscularly (Sluka model), as an experimental fibromyalgia model. METHODS: Male Sprague-Dawley rats received two intramuscular injections of acidic saline (pH 4.0) into the gastrocnemius muscle. After the development of tactile allodynia demonstrated by decreased paw withdrawal threshold to von Frey filaments, anxiety-like behaviours were evaluated using the open field test and the elevated plus maze test. RESULTS: Sluka model rats exhibited anxiety-like behaviours in the open field test (significant decreases in distance travelled and time spent in the central area, and significant increases in time spent in the wall area) and the elevated plus maze test (significant decreases in time spent in the open arms and significant increases in time spent in the closed arms). A single oral dose of mirogabalin (3 or 10 mg/kg) significantly alleviated and normalised these anxiety-like behaviours. CONCLUSIONS: Sluka model rats exhibited anxiety-like behaviours in the open field test and the elevated plus maze test, but mirogabalin alleviated these behaviours. Mirogabalin might thus have the potential to relieve anxiety in fibromyalgia patients.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Bridged Bicyclo Compounds/pharmacology , Animals , Calcium Channels, L-Type , Elevated Plus Maze Test , Fibromyalgia/chemically induced , Fibromyalgia/drug therapy , Male , Neuralgia/drug therapy , Open Field Test , Pain Threshold/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.
Subject(s)
Analgesics/therapeutic use , Receptors, Opioid, mu/agonists , Analgesics/pharmacology , Animals , Disease Models, Animal , Humans , MiceABSTRACT
We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.
Subject(s)
Analgesics, Opioid/therapeutic use , Indole Alkaloids/therapeutic use , Receptors, Opioid, mu/therapeutic use , Analgesics, Opioid/pharmacology , Animals , Indole Alkaloids/pharmacology , Mice , Receptors, Opioid, mu/agonistsABSTRACT
Prostaglandin E2 (PGE2) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE2 synthesis inhibitor, compound I, 2-methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE2 selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2 signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE2 receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2 signaling, especially through the EP4 receptor, and PGI2 signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Dinoprostone/metabolism , Epoprostenol/metabolism , Hyperalgesia/drug therapy , Pain/drug therapy , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Cyclooxygenase 2 Inhibitors/therapeutic use , Dinoprostone/antagonists & inhibitors , Epoprostenol/antagonists & inhibitors , Inflammation/drug therapy , Macrophages/drug effects , Male , Rats , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Signal Transduction/drug effects , Sulfonamides/therapeutic useABSTRACT
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.
Subject(s)
Action Potentials , Genetic Diseases, Inborn , Mutation, Missense , NAV1.9 Voltage-Gated Sodium Channel , Neuralgia , Amino Acid Substitution , Animals , Asian People , Cell Line , Family , Female , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/metabolism , Genetic Diseases, Inborn/physiopathology , Genetic Linkage , Genetic Loci , Humans , Japan , Male , Mice , Mice, Transgenic , NAV1.9 Voltage-Gated Sodium Channel/genetics , NAV1.9 Voltage-Gated Sodium Channel/metabolism , Neuralgia/genetics , Neuralgia/metabolism , Neuralgia/physiopathology , Pedigree , SyndromeABSTRACT
Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antipyretics/therapeutic use , Arthritis, Experimental/drug therapy , Dinoprostone/biosynthesis , Fever/drug therapy , Inflammation/drug therapy , Piperidines/therapeutic use , Quinolines/therapeutic use , A549 Cells , Animals , Cell Line, Tumor , Disease Models, Animal , Fever/chemically induced , Humans , Lipopolysaccharides , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Rats , Rats, Inbred Lew , Rats, Sprague-DawleyABSTRACT
Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.
Subject(s)
Arthritis, Experimental/drug therapy , Benzothiazoles/therapeutic use , Dinoprostone/biosynthesis , Fever/drug therapy , Piperidines/therapeutic use , 6-Ketoprostaglandin F1 alpha/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzothiazoles/adverse effects , Benzothiazoles/pharmacology , Depression, Chemical , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Guinea Pigs , Imidazoles/therapeutic use , Indomethacin/therapeutic use , Inflammation/drug therapy , Macrophages/metabolism , Pain/drug therapy , Peptic Ulcer/drug therapy , Phenanthrenes/therapeutic use , Piperidines/adverse effects , Piperidines/pharmacology , Stimulation, Chemical , Thromboxane B2/metabolismABSTRACT
A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin.
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/drug effects , Piperidines/chemical synthesis , Piperidines/pharmacology , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/pharmacology , Animals , Humans , Inhibitory Concentration 50 , Mexiletine/chemistry , Mexiletine/pharmacology , Mice , Molecular Structure , Piperidines/chemistry , Voltage-Gated Sodium Channel Blockers/chemistryABSTRACT
To begin to understand the relationship between disease progression and pain in pancreatic cancer, transgenic mice that develop pancreatic cancer due to the expression of the simian virus 40 large T antigen under control of the rat elastase-1 promoter were examined. In these mice precancerous cellular changes were evident at 6 weeks and these included an increase in: microvascular density, macrophages that express nerve growth factor and the density of sensory and sympathetic fibers that innervate the pancreas, with all of these changes increasing with tumor growth. In somatic tissue such as skin, the above changes would be accompanied by significant pain; however, in mice with pancreatic cancer, changes in pain-related behaviors, such as morphine-reversible severe hunching and vocalization only became evident at 16 weeks of age, by which time the pancreatic cancer was highly advanced. These data suggest that in mice as well as humans, there is a stereotypic set of pathological changes that occur as pancreatic cancer develops, and while weight loss generally tracks disease progression, there is a significant lag between disease progression and behaviors indicative of pancreatic cancer pain. Defining the mechanisms that mask this pain in early and mid-stage disease and drive the pain in late-stage disease may aid in earlier diagnosis, survival, and increased quality of life of patients with pancreatic cancer.
Subject(s)
Body Weight , Neovascularization, Pathologic/pathology , Pain/physiopathology , Pancreas/innervation , Pancreas/physiopathology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/physiopathology , Animals , Disease Progression , Macrophage Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pain/diagnosis , Pain/etiology , Pancreas/blood supply , Pancreas/pathology , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/complications , Precancerous Conditions/blood supply , Precancerous Conditions/pathology , Precancerous Conditions/physiopathology , Statistics as TopicABSTRACT
UNLABELLED: Cancer pain is a significant clinical problem because it is the first symptom of disease in 20% to 50% of all cancer patients, and 75% to 90% of patients with advanced or terminal cancer must cope with chronic pain syndromes related to failed treatment and/or tumor progression. One of the most difficult to treat cancer pains is metastatic invasion of the skeleton that can generate ongoing and bone breakthrough pain, which represents one of the most debilitating cancer-related events. Because bradykinin has been shown to be released in response to tissue injury and plays a significant role in driving acute and chronic inflammatory pain, we focused on bradykinin antagonists in a model of bone cancer pain. In our model of bone cancer, which involves the injection and confinement of 2472 sarcoma cells to the mouse femur, pharmacologic blockade of the bradykinin B1 receptor is effective in reducing pain-related behaviors at both early and advanced stages of bone cancer. PERSPECTIVE: Bone cancer pain can be severe and difficult to control fully. With a mouse model of bone cancer pain we demonstrate that pharmacologic blockade of the bradykinin B1 receptor is effective in reducing bone cancer pain-related behaviors, suggesting that B1 antagonists might be useful in attenuating bone cancer pain in humans.
Subject(s)
Bone Neoplasms/complications , Bradykinin B1 Receptor Antagonists , Bradykinin/analogs & derivatives , Pain/drug therapy , Sarcoma/complications , Animals , Bradykinin/pharmacology , Injections, Subcutaneous , Male , Mice , Mice, Inbred C3H , Neoplasm Transplantation , Pain/etiologyABSTRACT
Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain.
Subject(s)
Antibodies/pharmacology , Bone Neoplasms/complications , Bone Neoplasms/secondary , Nerve Growth Factor/antagonists & inhibitors , Pain Management , Prostatic Neoplasms/complications , Prostatic Neoplasms/therapy , Analgesics, Opioid/therapeutic use , Animals , Bone Remodeling , Bone and Bones/innervation , Brain/metabolism , Cell Line, Tumor , Disease Progression , Dogs , Male , Mice , Mice, Nude , Morphine/therapeutic use , Nerve Growth Factor/genetics , Nerve Growth Factor/immunology , Pain/drug therapy , Pain/etiology , Prostatic Neoplasms/pathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Skin/innervationABSTRACT
Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.
Subject(s)
Bone Neoplasms/pathology , Neurons, Afferent/pathology , Pain/etiology , Pain/pathology , Polyneuropathies/etiology , Polyneuropathies/pathology , Afferent Pathways/chemistry , Afferent Pathways/pathology , Animals , Bone Neoplasms/complications , Male , Mice , Mice, Inbred C3H , Neurons, Afferent/chemistryABSTRACT
Bone cancer pain can be difficult to control, as it appears to be driven simultaneously by inflammatory, neuropathic and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and neuropathic pain states, we focused on a novel NGF sequestering antibody and demonstrated that two administrations of this therapy in a mouse model of bone cancer pain produces a profound reduction in both ongoing and movement-evoked bone cancer pain-related behaviors that was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine. This therapy also reduced several neurochemical changes associated with peripheral and central sensitization in the dorsal root ganglion and spinal cord, whereas the therapy did not influence disease progression or markers of sensory or sympathetic innervation in the skin or bone. Mechanistically, the great majority of sensory fibers that innervate the bone are CGRP/TrkA expressing fibers, and if the sensitization and activation of these fibers is blocked by anti-NGF therapy there would not be another population of nociceptors, such as the non-peptidergic IB4/RET-IR nerve fibers, to take their place in signaling nociceptive events.