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PubMed2002

A preclinical model of minimal residual cancer in the muscle highlights challenges associated with adenovirus-mediated p53 gene transfer.

PURPOSE: Clinical studies have revealed that tumors may recur at the operative site if radioresistant p53 mutation-positive residual disease remains in the body after treatment. Destruction of these remaining malignant cells, which can be present in both mucosal and deep muscle margins, may be achieved using p53-mediated gene transfer techniques. Most preclinical studies designed to assess the feasibility of harnessing this approach have used s.c. tumor models in nude mice, but it is anticipated that transduction of tumor cells in the muscle in immune-competent hosts may be more difficult. EXPERIMENTAL DESIGN: To address this point a new rodent model of residual cancer was established implanting PDVC57B tumor cells to create multiple tumor tracts in the muscle of syngeneic immune-competent C57Bl/6 mice. s.c. tumors and a s.c. model of residual disease were used as comparators. RESULTS: In the s.c. model of residual disease a single administration of 5 x 10(10) viral particles of Ad5CMV-p53 suppressed the growth of encapsulated tumor at the treatment site in six of six animals, but two of these animals had viable nests of tumor outside of the encapsulated zone. However, Ad5CMV-p53 had no apparent effect on tumor cell progression in the model of residual cancer in the muscle. Creating the muscle model of residual cancer with a lower number of cells in the initial inoculum showed that immune-mediated effects, as well as those attributable to the transgene, are important in preventing tumor outgrowth. The frequency of transduction of tumor cells in the muscle, as determined after administration of Ad-beta-galactosidase, was typically <3% and markedly different from the 20% transduction observed for the s.c. tumor model. CONCLUSIONS: These studies highlight the need to devise strategies to improve delivery of adenovirus-mediated gene transfer to nests of tumor in muscle before this modality is used to treat residual cancer at this site. These may involve approaches such as intravascular delivery, strategies to improve vector diffusion, or combination with chemotherapy or radiotherapy to enhance gene delivery at these less accessible sites of disease.

Adenoviridae↗

PubMed2005

The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism.

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

Absorptiometry, Photon↗

PubMed2004

Effects of a low dose of ethanol in an animal model of premenstrual anxiety.

Low (1 mM), but not 10 mM, concentrations of ethanol selectively potentiate current gated by alpha(4)beta(2)delta subunit combinations of the gamma-aminobutyric acid type A (GABA(A)) receptor, a subtype increased in hippocampus after withdrawal from progesterone in a rodent model of premenstrual anxiety. In the current study, we tested the hypothesis that the anxiolytic effect of ethanol would exhibit a similar dose-response effect by using the acoustic startle response (ASR) and elevated plus-maze as behavioral models. To this end, adult, female rats were tested (1) 24 h after removal of a progesterone-filled capsule implanted subcutaneously for 21 days (progesterone withdrawal) or (2) on the day of diestrus, a low hormone state. Low doses of ethanol (0.2-0.4 mg/kg) produced a significant 60%-70% decrease in the ASR only in animals undergoing progesterone withdrawal. However, higher doses of ethanol (0.8-1.2 g/kg) were ineffective in these animals, resulting in an "inverted U" ethanol dose effect similar to that observed at recombinant alpha(4)beta(2)delta subunit combinations of the GABA(A) receptor. Consistent with these findings, significant 70% attenuation of the ASR was also achieved after progesterone withdrawal with 3 mg/kg of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a GABA(A) receptor partial agonist with greater potency at alpha(4)betadelta receptors than at other known isoforms. In contrast, this partial agonist was not anxiolytic in control animals. These results support the suggestion that very low doses of ethanol are anxiolytic in a model of premenstrual anxiety, whereas higher, potentially sedative, doses are without effect. The results may be relevant for altered ethanol sensitivity during premenstrual syndrome, when increased ethanol consumption has been reported.

Animals↗

PubMed2005

Behavioral, physical, and demographic changes in Drosophila populations through dietary restriction.

Dietary restriction (DR) is a valuable experimental tool for studying the aging process. Primary advancement of research in this area has relied on rodent models, but attention has recently turned toward Drosophila melanogaster. However, little is known about the baseline effects of DR on wild-type Drosophila and continued experimentation requires such information. The findings described here survey the effects of DR on inbred, wild-type populations of Canton-S fruit flies and demonstrate a robust effect of diet on longevity. Over a circumscribed range of dietary conditions, healthy lifespan varies by as much as 121% for wild-type Drosophila females. Significant differences are also observed for male flies, but the magnitude of the DR effect is less robust. Mortality analyses of the survivorship data reveal that this variation in lifespan can be attributed to a modulation of the rate parameter for the mortality function - a change in the demographic rate of aging. Since the feeding of fruit flies is less easily controlled than that of rodents, this research also addresses the validity of applying a DR model to Drosophila populations. Feeding and body weight data for flies given the various dietary conditions surveyed indicate that Drosophila on higher-calorie diets consume a similar volume of food to those on a low-calorie diet, resulting in different levels of calorie intake. Fertility and activity levels demonstrate that the diets surveyed are comparable, and that increasing the calorie content of laboratory food up to twice the normal concentration is not pathologic for experimental fly populations.

Aging↗

PubMed2006

Chemical constituents and antifilarial activity of Lantana camara against human lymphatic filariid Brugia malayi and rodent filariid Acanthocheilonema viteae maintained in rodent hosts.

Lymphatic filariasis continues to be a major health problem in tropical and subtropical countries. A macrofilaricidal agent capable of eliminating adult filarial parasites is urgently needed. In the present study, we report the antifilarial activity in the extract of stem portion of the plant Lantana camara. The crude extract at 1 g/kg for 5 days by oral route killed 43.05% of the adult Brugia malayi parasites and sterilized 76% of surviving female worms in the rodent model Mastomys coucha. A 34.5% adulticidal activity along with sterilization of 66% of female worms could be demonstrated in the chloroform fraction. Remarkable antifilarial activity was observed in the adult B. malayi transplanted gerbil model where up to 80% of the adult worms could be killed at the same dose and all the surviving female parasites were found sterilized. The extract was also found effective against a subcutaneous rodent filariid Acanthocheilonema viteae maintained in Mastomys coucha, where it exerted strong microfilaricidal (95.04%) and sterilization (60.66%) efficacy with mild macrofilaricidal action. Two compounds, oleanonic acid and oleanolic acid, isolated from hexane and chloroform fractions showed LC100 at 31.25 and 62.5 mug/ml, respectively, on B. malayi in vitro. This is the first ever report on the antifilarial efficacy of Lantana camara.

Animals↗

PubMed2005

Current Therapy for Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth (CMT), or heritable peripheral neuropathies, is among the most frequent genetic neuromuscular disorders, with a prevalence of approximately 1:2500. Since 1991, remarkable advances have occurred in determining the precise genetic cause of many forms of CMT and in generating animal models of many of these disorders. However, these advances have not yet resulted in cures for CMT. Recently, potential treatments for the most common form of CMT, CMT-1A, have been shown in rodent models of the disorder. Treatment with onapristone, a progesterone antagonist, has improved the neuropathy of the CMT-1A rat. Treatment with large doses of ascorbic acid (vitamin C) has improved the neuropathy of the CMT-1A mouse. Multicentric trials with ascorbic acid are likely to start in the near future to assess if vitamin C supplementation is effective and what is the dosage required in humans to improve neurologic disability. Because of potential side effects with antiprogesterone therapy, particularly in women of child- bearing age, research is actively proceeding with progesterone antagonists to develop safe medications that also can be used in clinical trials of CMT-1A. Although no cures are available for CMT, there are many important treatments available for patients with CMT that can improve their quality of life and help them maintain their independence. Some of these therapies involve physiatry and orthopedic surgery. Others involve pain management. Lastly, there are potential concerns about medications or lifestyle issues that may exacerbate CMT. All of these issues will be discussed.

Journal Article↗

PubMed2002

Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.

Bile acid biosynthesis is regulated by both feed-forward and feedback mechanisms involving a cascade of nuclear hormone receptors. Feed-forward regulation of the rate limiting enzyme in bile acid biosynthesis is provided by oxysterols through liver-X-receptor alpha (NR1H3), while feedback regulation is provided by bile acids through farnesoid-X-receptor (FXR) (NR1H4). The Syrian golden hamster provides a useful model for studying lipid metabolism. The hamster metabolizes and transports dietary cholesterol in a similar manner to humans, with the resulting lipid profile being more similar to the human profile than that of other rodent models. Cloning of Fxr from Syrian golden hamster revealed four hamster Fxr splice variants that altered the N-terminal activation domain or the hinge region between the DNA and ligand binding domains. Human genomic sequence and data from hamster Fxr were used to identify and clone a novel human FXR isoform resulting from the use of an alternative promoter. RNA expression analysis indicates that the two human FXR isoforms are differentially expressed in developmental and tissue-specific patterns and are likely to provide a mechanism for cell-specific FXR-dependent transcriptional activity.

Alternative Splicing↗

PubMed2003

Desipramine treatment reduces the long-term behavioural and neurochemical sequelae of early-life maternal separation.

Primate and rodent models of maternal separation have shown that repeated postnatal separation of young from the mother results in long-term changes to neurohormonal systems relevant to depression. To date, however, it remains unclear whether rodents that experience postnatal maternal separation display specific behavioural or biochemical features of depression in adulthood and whether these changes can be prevented by treatment with antidepressant drugs. We report here that maternally separated mice showed significantly shorter swim times on the forced swim test and significantly lower levels of brain-derived neurotrophic factor in dentate gyrus and CA3 regions of the hippocampus compared to control mice when assessed in adulthood. Neither of these differences was apparent in maternally separated mice that received chronic treatment with the antidepressant desipramine after maternal separation. These results suggest that intervention following early stress may eliminate the long-term vulnerability to behavioural and biochemical dysfunction that occurs following this early chronic stress.

Animals↗

PubMed2003

Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model.

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.

Acetic Acid↗

PubMed1990

Preclinical antimycotic activity of SDZ 89-485: a new orally and topically effective triazole.

SDZ 89-485 is a new orally and topically active triazole antifungal with efficacy superior to reference compounds in most animal infection models used for preclinical comparison of antifungals. The compound inhibits mycelial transformation of Candida albicans in vitro at MIC50 concentrations of 0.006 and 0.00019 mg l-1 in MEM and NYP medium, respectively. In rodent models of vaginal candidosis SDZ 89-485 was significantly more active than reference compounds after various oral or topical treatment regimens, with ED50 values ranging from 0.09 to 0.79 mg kg-1 and 0.01% active ingredient, respectively. When administered orally, the efficacy of SDZ 89-485 was superior to, or as good as that of the reference compounds in several murine models of systemic candidosis, sporotrichosis and histoplasmosis. In murine aspergillosis, using the kidney as the target organ. SDZ 89-485 was as active as itraconazole. Guinea pig trichophytosis was more responsive to oral fluconazole and itraconazole than to oral SDZ 89-485.

Animals↗

PubMed2001

Mechanisms of corneal graft rejection: the sixth annual Thygeson Lecture, presented at the Ocular Microbiology and Immunology Group meeting, October 21, 2000.

The history of corneal transplantation reaches back over 150 years. Kissam performed one of the first penetrating keratoplasties when he transplanted a pig cornea onto a human in 1838. Only two interrupted sutures were used, and the surgery was performed without anesthesia! In retrospect, no one would be surprised to learn that the porcine corneal xenograft was rejected. Thirty years later, May transplanted rabbit corneal grafts to humans, but concluded that the failures in the first 24 attempts were the result of "imperfect technique and the inability to keep the eyes properly bandaged." The first documented report of a successful penetrating keratoplasty in a human subject was performed by Zirm in 1905. As we enter the new millennium, corneal transplantation remains the oldest, most common, and, arguably, the most successful form of solid tissue transplantation. In the United States alone, approximately 36,000 corneal transplants are performed each year. The success rate for corneal transplants is in excess of 90% in uncomplicated cases, even though HLA tissue typing is not performed and systemic immunosuppressive drugs are not administered. In spite of this extraordinary success, immune rejection remains the leading cause of corneal graft failure. Many inferences about the immunobiology of corneal graft rejection have been based on clinical observations; however, confirmation of these hypotheses requires prospective studies under controlled settings. The prudent use of animal models has fostered analytic studies on the immunobiology of corneal allografts without the complicating and confounding effects of topical steroids that are typically used on most keratoplasty patients. Although animal models of penetrating keratoplasty have been in use for almost a half-century, until recently, progress in understanding the immune mechanisms of corneal graft rejection has been slow. However, the widespread use of rodent models of orthotopic corneal transplantation has shed new light on the pathogenesis of corneal graft rejection.

Animals↗

PubMed2000

Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation.

Expression of the inducible isoform of nitric oxide (NO) synthase, and the formation of peroxynitrite from NO and superoxide are responsible for some of the pathophysiological alterations seen during reperfusion injury and in various inflammatory conditions. Some of the effects of peroxynitrite are related to DNA single-strand breakage, and activation of poly (ADP-ribose) synthetase. Here we investigated the effect of nicaraven (2(R,S)-1,2-bis(nicotinamido)propane), a known hydroxyl radical scavenger compound and neuroprotective agent, on several NO- and peroxynitrite related pathways in vitro, and in shock and inflammation in vivo. Nicaraven, at 10 microM-10 mM, failed to inhibit the peroxynitrite-induced oxidation of dihydrorhodamine 123, indicating that the agent does not act as a scavenger of peroxynitrite. In RAW murine macrophages stimulated with peroxynitrite, nicaraven caused a dose-dependent, slight inhibition of poly (ADP-ribose) synthetase activation, possibly due to a direct inhibitory effect on the catalytic activity of poly (ADP-ribose) synthetase. Nicaraven partially protected against the peroxynitrite-induced suppression of mitochondrial respiration in RAW macrophages and caused a slight, dose-dependent inhibition of nitrite production in RAW macrophages stimulated with bacterial lipopolysaccharide. We next investigated the effect of nicaraven treatment in a variety of models of inflammation and reperfusion injury. Nicaraven (at 10-100 microg/paw) exerted significant protective effects in the carrageenan-induced paw edema model and (at 100 mg/kg i.v.) reduced neutrophil infiltration and histological damage in splanchnic artery occlusion-reperfusion injury. However, nicaraven failed to alter the course of hemorrhagic and endotoxic shock and arthritis in rodent models. The current data indicate the limited role of hydroxyl radicals in the pathogenesis of the inflammatory conditions tested.

Animals↗

PubMed2004

Identification and characterization of potential human carcinogens using B6.129tm1Trp53 heterozygous null mice and loss of heterozygosity at the Trp53 locus.

Rodent models are often used as surrogates for humans in toxicology and cancer research. Transgenic mice have been useful for studying gene function by loss of function or gain of function through mutation or overexpression. Thus, transgenic or genetically altered mouse models could play an important role in understanding environment-gene interactions. Wild-type Trp53 protein is critical for cell function and maintaining integrity of the genome, which suppresses cancer in humans and rodents. Mice heterozygous for a Trp53 null and a wild-type allele are p53 haplo-insufficient. This reduction in p53 protein results in deficiencies in cell cycle check-point control and induction of apoptosis. p53 Haplo-insufficient mice do not immediately develop neoplasia as a result of this signalling dysregulation. However, exposure to mutagenic carcinogens induces neoplasia during the period in which unexposed, co-isogenic haplo-insufficient and homozygous wild-type mice are free from neoplasia. These observations provide a basis for evaluation of p53 haplo-insufficient mice for mechanism-based identification of carcinogens. Maximum tolerated doses (MTD) determined and used for 2-year NCI/NTP cancer bioassays and/or by 28-day toxicokinetic studies to predict MTD for subchronic studies were, generally, effective in inducing neoplasia with reduced latency in 26-week exposure studies in p53 haplo-insufficient mice. The latency of tumour development may be shortened by requiring only an additional genetic alteration (or alterations) in p53 (mutation or loss of heterozygosity (LOH) involving the Trp53 locus) or in other tumour-suppressor genes by mutation or inactivation. LOH is a loss of genetic loci through chromosomal aberrations and reduction to homozygosity that often results in loss of tumour-suppressor genes. Interspecies extrapolation between rodents and humans is difficult owing to the possibility of species differences, but demonstration of an operational mechanism, such as mutation or loss of p53 function through LOH, may help in reducing uncertainty and, thus, lead to identification of carcinogens of presumed risk to humans.

Animals↗

PubMed2004

Temporal characterisation of amphetamine-induced dopamine release assessed with [11C]raclopride in anaesthetised rodents.

Competition between endogenous neurotransmitters and radiolabelled tracers, as measured by positron emission tomography (PET), may provide a measure of endogenous neurotransmitter flux in vivo. For example, carbon-11 labelled raclopride has been effectively used to monitor dopamine release following pharmacological and behavioural manipulations. The current study describes a rodent model of amphetamine-induced [11C]raclopride reduction, which allowed the characterisation of the dose-response and temporal dynamics of this reduction over a 24-h time course. Over the range studied, a monotonic dose-response relationship between amphetamine dose and [11C]raclopride reduction was observed. When compared with previously published microdialysis data, an approximate 16% reduction in [11C]raclopride binding potential was associated with a approximately 25-fold increase in extracellular dopamine. A reduction of 20-30% in raclopride binding was observed 30 min after amphetamine injection (4 mg/kg i.p.). This reduction in [11C]raclopride binding persisted for 4 h but returned to baseline by 8 h. The data suggest a persistent amphetamine-induced raclopride displacement in rodents and reinforce findings from nonhuman primates that a simple competitive occupancy model may not adequately explain the temporal characteristics of the amphetamine-induced decrease in radiotracer binding.

Amphetamine↗

PubMed2000

Gene transfer for neuroprotection in animal models of Parkinson's disease and amyotrophic lateral sclerosis.

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MN) and dopaminergic (DA) neurons, neurons which selectively die in amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). GDNF gene delivery has been studied in rodent models of ALS and PD. In a mouse model of ALS, implantation of myoblasts retrovirally transduced with GDNF into hindlimb muscles at 6 weeks of age, i.e. prior to the onset of disease symptoms, increased the number of large MNs that maintained projections to treated muscles at 18 weeks of age. GDNF-treated mice also performed better on tests of motor function and had a delayed onset of disease. In a progressive degeneration rat model of PD, effects of in vivo GDNF gene therapy using an adenoviral vector (AdGDNF) were studied in young and aged rats. AdGDNF protected DA neurons against the neurotoxin, 6-hydroxydopamine (6-OHDA), and was effective whether injected either before or after 6-OHDA damage had commenced. However, if AdGDNF was injected prior to 6-OHDA, it was most effective in protecting against DA-dependent changes in the brain when injected near the terminals of the DA neurons. In contrast, if 6-OHDA damage had already commenced, AdGDNF was most effective if injected near the DA soma. These studies suggest that GDNF gene delivery into specific sites in the CNS or into muscle where MNs have access to secreted GDNF may slow the progression of PD and ALS, respectively. Neurotrophic factor gene therapy offers novel interventions not only for PD and ALS, but also other neurodegenerative diseases and injuries to the nervous system.

Amyotrophic Lateral Sclerosis↗

PubMed2005

The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis.

CCR2 has been widely considered as a potential therapeutic target for autoimmune disease, particularly rheumatoid arthritis, and various CCR2 blocking agents have been developed, some of which have entered clinical trials. In this review, we examine the relevant information regarding the role of CCR2, and to a lesser extent of the closely related chemokine receptor CCR5, in the immunopathogenesis of collagen-induced arthritis, an animal model of rheumatoid arthritis. Experimental evidence showing that CIA is accelerated and exacerbated when CCR2 is genetically inactivated (knockout mice) or blocked with specific antibodies warrant additional investigations before the relevance of the findings in rodent models can be applied to human patients with RA.

Animals↗

PubMed2004

Neurological basis of drug dependence and its effects on the immune system.

This review summarizes some of the major points discussed by participants in the symposium session on effects of drugs of abuse on both neurologic and immune systems. Speakers in this session are acknowledged experts and biomedical scientists in the rapidly expanding field of studies of abuse drugs on immune responses, especially as related to the effects of increased susceptibility to infections, including opportunistic infections related to AIDS. The important topics specifically discussed in this session included discussion of the neurobiology of addiction in regards to cell biology of the central nervous system and altered physiological and behavioral functions. Using experimental rodent models, description of effects of heroin or cocaine, especially self administration of these drugs, on immune cell deficiency and HPA activation, was reviewed as well as effects on important proinflammatory cytokines like TNFalpha. A model system concerning acute morphine withdrawal on ex vivo immune responses by murine cells was described in detail, including effects of such withdrawal on splenocyte or macrophage responses to bacterial LPS. The chronic exposure of rodents to a drug such as cocaine or morphine was described in terms of CNS neurochemical alterations as related to immune responsiveness. The effects of the legal drug nicotine, now known to be the addictive substance of cigarette smoke, was discussed in regards to effects on both the neurologic and immunologic system in rodents in terms of antibody formation and T cell function, related to HBA activation and proinflammatory cytokine responses. It is apparent from this session, that studies concerning the impact of drugs of abuse on the brain-immune-axis and relationship to the immune system constitute a rapidly expanding area and warrant further interest of biomedical scientists.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy.

Neuropathic pain, due to peripheral nerve damage, can include allodynia (perception of innocuous stimuli as being painful), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous pain, often accompanied by sensory deficits. Plasticity in transmission and modulatory systems are implicated in the underlying mechanisms. The Kim and Chung rodent model of neuropathy (Kim and Chung, Pain 50 (1992) 355) employed here involves unilateral tight ligation of two (L5 and L6) of the three (L4, L5, and L6) spinal nerves of the sciatic nerve and reproducibly induced mechanical and cold allodynia in the ipsilateral hindpaw over the 14 day post-operative period. In vivo electrophysiological techniques have then been used to record the response of dorsal horn neurones to innocuous and noxious electrical and natural (mechanical and thermal) stimuli after spinal nerve ligation (SNL). Activation of voltage-dependent calcium channels (VDCCs) is critical for neurotransmitter release and neuronal excitability, and antagonists can be antinociceptive. Here, for the first time, the effect of N- and P-type VDCC antagonists (omega-conotoxin-GVIA and omega-agatoxin-IVA, respectively) on the evoked dorsal horn neuronal responses after neuropathy have been investigated. Spinal omega-conotoxin-GVIA (0.1-3.2 microg) produced prolonged inhibitions of both the electrically- and low- and high-intensity naturally-evoked neuronal responses in SNL and control rats. Spinal omega-agatoxin-IVA (0.1-3.2 microg) also had an inhibitory effect but to a lesser extent. After neuropathy the potency of omega-conotoxin-GVIA was increased at lower doses in comparison to control. This indicates an altered role for N-type but not P-type VDCCs in sensory transmission after neuropathy and selective plasticity in these channels after nerve injury. Both pre- and post-synaptic VDCCs appear to be important.

Animals↗