Director's Report to the National Advisory Council on Drug Abuse
Role for GDNF in Biochemical and Behavioral Adaptations to Drugs of Abuse
Drs. David Russell and Eric Nestler and their research team at the Yale University examined a role for Glial-Derived Neurotrophic Factor (GDNF) in adaptations to drugs of abuse. Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic brain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusion of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of phosphoRet, the protein kinase that mediates GDNF signaling in the VTA. Together, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increases the behavioral sensitivity to subsequent drug exposure. Messer, C.J., Eisch, A.J., Carlezon, W.A. Jr., Whisler, K., Shen, L., Wold, D.H., Westphal, H., Collins, F., Russell, D.S., and Nestler, E.J. Role for GDNF in Biochemical and Behavioral Adaptations to Drugs of Abuse. Neuron, 26(1), pp. 247-257, 2000.
Mechanisms Responsible for Methamphetamine-Induced Rapid Decrease in Dopamine Transporter Function
Single and multiple high-dose administrations of methamphetamine (METH) decrease dopamine (DA) transporter function, as assessed in striatal synaptosomes (approximately 33% and 78% reductions, respectively). These effects occur within 60 minutes after in vivo treatment and persist even after METH is removed from the synaptosomal preparation. The large reduction in DAT function after multiple METH injections appears to have two separate components with distinct underlying mechanisms. Phase I occurs after either a single or multiple METH administrations and is not dependent on drug-induced changes in dopaminergic function or hyperthermia. It is hypothesized that phase I is due to a METH-induced internalization of DAT causing a temporary loss of transporter function. Phase II only occurs after multiple METH administrations and is dependent on activation of DA receptors, hyperthermia and free radical formation. Even though there is no loss of DAT protein, it is possible this phase II response of DAT to METH is somehow related to the neurotoxic potential of this drug, as similar factors are necessary for this drug to induce long-term deficits in monoamine systems after multiple METH treatments. The precise nature of these two phases of METH-induced reduction in DAT activity requires further study and may be important for understanding both the short- and long-term consequences of abusing this drug. Metzger, R.R., Haughey, H.M., Wilkins, D.G., Gibb, J.W., Hanson, G.R., and Fleckenstein, A.E. Methamphetamine-Induced Rapid Decrease in Dopamine Transporter Function: Role of Dopamine and Hyperthermia. J. Pharmacol. Exp. Ther., 295(3), pp. 1077-1085, 2000.
Pigment Measurement is Important for Hair Testing for Several Drugs of Abuse
In rats with pigmented hair, cocaine, ecogonine methyl ester (EME) and norcocaine (NCOC) were detected in dose-related concentrations whereas in rats with non-pigmented hair none of these were detected. In rats with pigmented hair, cocaine was twice as likely as its metabolite benzoylecgonine (BE) to be detected. Melanin binds to basic drugs with a net positive charge. Cocaine concentrations in pigmented hair peaked after cocaine disappears from the blood. In rats with pigmented hair, maximal hair concentrations of cocaine were found three days after serum concentrations became undetectable. In rats with non-pigmented hair, concentrations of cocaine were undetectable for two days. In rats, while amphetamine binds preferentially to pigmented hair, its non-basic analog, N-acetylamphetamine, is taken up equally in both pigmented and non-pigmented hair. In mice, while the cation 45CA2 associated with melanocytes and melanosomes of forming pigmented hair within 5 minutes of dosing, the anion 38Cl- did not associate in the hair of either pigmented or non-pigmented hair. Hubbard, D.L., Wilkins, D.G., and Rollins, D.E. The Incorporation of Cocaine and Metabolites into Hair: Effects of Dose and Hair Pigmentation. Drug Metab. Dispos., 28, pp. 1464-1469, 2000.
Heroin Modulation of Immune Status
Heroin use is associated with an increased incidence of several types of infections, including HIV, yet few studies have assessed whether heroin produces pharmacological alterations of immune status that might contribute to the increased rate of infections among heroin users. Two recent studies by Dr. Donald Lysle and his colleagues have evaluated the immunomodulatory effects of a single heroin injection in the rat. The first study investigated whether a single heroin administration produces dose-dependent alterations in immune status. The results show that heroin produces a dose-dependent, naltrexone-reversible suppression in stimulated proliferation of T-cells, B-cells, production of interferon-g, and cytotoxicity of natural killer (NK) cells in the spleen. Thus, heroin affects both functional and phenotypic measures of immune status. Fecho, K., Nelson, C.J., and Lysle, D.T. Phenotypic and Functional Assessments of Immune Status in the Rat Spleen Following Acute Heroin Treatment. Immunopharmacology, 46, pp. 193-207, 2000.
A second study examined the rate of splenocyte death by necrosis or apoptosis. The results showed that a single injection of heroin decreased the total number of leukocytes in the spleen in a dose-dependent, naltrexone-reversible manner. Moreover, the heroin-induced decrease in splenic leukocytes was not associated with an increase in circulating leukocytes. Fecho, K., and Lysle, D.T. Heroin-Induced Alterations in Leukocyte Numbers and Apoptosis in the Rat Spleen. Cellular Immunology, 202, pp. 113-123, 2000.
Endomorphin-1, Antinociception and Immune Modulation
Central opioid receptors have been known for some time to be involved in immunomodulation. However, only recently has an endogenous agonist possessing high selectivity and affinity for the mu opioid receptor, endomorphin-1, been identified. Little is known about the immunomodulatory and antinociceptive effects of endomorphin-1. Dr. Donald Lysle and his colleagues found in rats that endomorphin-1 produced naltrexone-reversible antinociception in both the hotplate assay and in the warm water tail withdrawal assay. However, there were no immunomodulatory effects up to 120 minutes after injection. These observations suggest that it may be possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the m-opioid receptor. Carrigan, K.A., Nelson, C.J. and Lysle, D.T. Endomorphin-1 Induces Antinociception without Immunomodulatory Effects in the Rat. Psychopharmacology, 151, pp. 299-305, 2000.
Methamphetamine Neurotoxicity Has Behavioral Consequences in Rats
Dr. John F. Marshall's group has been studying the degeneration of neurons in the somatosensory cortex after repeated methamphetamine. Given the general lack of studies of cognitive functioning after neurotoxic regimens of methamphetamine, they studied a spatial (hippocampus-dependent) and a cued (caudate nucleus-dependent) water maze task one week after a neurotoxic regimen of methamphetamine. Rats treated with methamphetamine had impaired acquisition of the cued, but not the spatial, task. By contrast, the methamphetamine group had impaired retention (tested 24 hr after acquisition) of the spatial task. The swimming speed was not affected in any tests, indicating that these effects were not due to impaired motor function. Autoradiography demonstrated that dopamine transporter was markedly reduced in the striatum, and serotonin transporter was reduced in the hippocampus. Thus, methamphetamine neurotoxicity has different consequences on hippocampus- and caudate-dependent memory tasks in rats. Schrder, N., and Marshall, J. Differential Effects of Methamphetamine-Induced Neurotoxicity on Hippocampus-Dependent and Caudate Nucleus-Dependent Memory Processes. Society for Neuroscience Abstracts, 26, Abstract 484.14, p. 1311, 2000.
More Evidence for Glutamate's Role in Addiction
Sensitization in rodents, defined as an enhanced response to a drug due to previous exposure to that drug, appears to model the enhanced drug-seeking behavior over time of human drug addicts. For example, the locomotor activation produced by amphetamine in rats increases with repeated daily injections, and the locomotor response to amphetamine remains sensitized indefinitely, despite stopping the daily injections. Dr. Paul Vezina's group is investigating the roles of the neurotransmitters glutamate and dopamine in sensitization. They found that microinjection of a compound that blocks glutamate reuptake into the nucleus accumbens enables enhanced locomotor responding to co-injection of a dopamine D1 receptor agonist (but not to a D2 agonist) in rats previously exposed to amphetamine. (Amphetamine releases dopamine, and thereby may lead to the activation of both D1 and D2 dopamine receptors.) This indicates that, in the n. accumbens, increased glutamate neurotransmission and activation of D1 dopamine receptors, neither of which is by itself sufficient, together contribute to the expression of locomotor sensitization by amphetamine. These new findings provide further evidence of the importance of the role of glutamate in the "switching" mechanism in the process of addiction. Kim, J-H., and Vezina, P. Rats Pre-Exposed to Amphetamine Show Enhanced Locomotion to a D1 Dopamine Receptor Agonist in the Nucleus Accumbens When Glutamate Reuptake is Inhibited. Society for Neuroscience Abstracts, 25, p. 2211, 1999.
Mechanism of Action of Bupropion
Since its approval in 1998 as a prescription drug in sustained-release oral form as a smoking cessation agent, mechanisms of the function of bupropion have been under investigation. Pharmacologically, the compound is an antidepressant structurally related to the phenethylamines, and is capable of causing an increase in extracellular dopamine in the nucleus accumbens, along with inhibiting the firing of noradrenergic neurons in the locus coerulus. It lacks binding affinity for the serotonin, dopamine, adrenergic, and muscarinic receptors. In a recent study by Dr. Billy Martin and his colleagues bupropion's action on nicotinic acetylcholine receptors was examined in-vitro (rat brain membrane binding and recombinant receptor subtypes in oocyte cells) and in-vivo (antinociception and behavioral testing). Electrophysiological cellular currents, induced by acetylcholine administration, were blocked at the alpha4beta2, alpha7, and alpha3beta2 receptor subtypes by various micromolar concentrations of bupropion, in a concentration dependent, reversible, noncompetitive, and voltage-independent manner. The relative order of receptor functional blocking observed was alpha3beta2>alpha4beta2>alpha7. The "alpha3"-containing subtypes have been shown from other work to be more resistant to functional inactivation by chronic nicotine exposure than alpha4beta2 or alpha7. Bupropion alone did not induce currents when acutely administered. In rat brain membranes, where the alpha4beta2 subtype is a predominant subtype, bupropion did not displace bound tritiated nicotine.
In behavioral tests of antinociception (hot plate and tail flick tests), motor effects, and convulsive seizures in mice, subcutaneous or intravenous injections of bupropion, prior to nicotine injections, antagonized at least some of the effects of injected nicotine, most notably its antinociceptive effects. The block of antinociception lasted approximately thirty to sixty minutes at a five mg/kg dose. This latter dose is similar to that previously used to show antidepressant behavioral effects in animals, and is higher than that required to produce dopamine reuptake blocking in animals. Future studies may address the question of the relative importance of nicotinic acetylcholine receptor blocking as compared to bupropion's effect on the dopamine and noradrenergic systems. Slemmer, J.E., Martin, B.L, and Damaj, M.I. The Journal of Pharmacology and Experimental Therapeutics, 295, pp. 321-327, 2000.
Opiate Receptors and Vascular Endothelial Cells
Studies have shown that in human and rat vascular endothelial cells, the mu opiate receptor is coupled to nitric oxide (NO) release and that these tissues exhibit stereo specific, saturable and naloxone-sensitive opiate binding sites. In a recent paper, Dr. George Stefano and his colleagues provide molecular evidence that mu-type opiate receptors are expressed in human vascular endothelia and that their expression can be regulated by pro-inflammatory cytokines. They observed that exposure of human endothelia to pro-inflammatory cytokines IL-1 led to a significant increase in the expression of mu transcript as well as in morphine-stimulated NO release measured ampherometrically. These findings advance our understanding of the physiological role of NO in the vascular and cardiac cellular function. Cadet, P., Bilfinger, T.V., Fimiani, C., Peter, D., and Stefano, G.B. Endothelium-New York, 7(3), pp. 185-191, 2000.
Opiates and Immune System
A recent study published by Dr. George Stefano and his associates demonstrates that in rat, after a latent period, brain morphinergic processes respond to peripheral immune challenges such as lipo-polysaccharide (LPS) injection or food deprivation stress. LPS, a bacterial product known to stimulate pro-inflammatory immune cascades, produced an increase in morphine levels in the rat brain in a time dependent manner with a peak reached at 36 hours. Increases in brain morphine levels were also observed in animals following 96 hours of food deprivation. This suggests that the latent period preceeding the increase in brain morphine levels is physiologically relevant as it probably allows the critical immune and neural excitatory processes to emerge and protect the organism from an overactive immune response. Goumon, Y., Bouret, S., Casares, F., Zhu, W., Beauvillain, J. and Stefano, G.B. Neuroscience Letters, 293, pp. 135-138, 2000.
Players in the Signal Transduction Pathways Induced by Cocaine and Morphine
G proteins are heterotrimeric proteins, made up of alpha, beta and gamma subunits. G proteins link receptors on the cell surface to intracellular signaling pathways. There are many genes encoding each G protein subunit, and so there are many versions of each subunit. The most unusual G alpha subunit is Gzalpha; it has the least similarity to others. When NIDA grantee Dr. Blendy and his co-workers made mice lacking this subunit, the animals showed several defects, including impaired platelet aggregation and altered responses to psychoactive drugs. The mutant mice exhibited a greatly exaggerated response to cocaine, a lowered response to the analgesic effects of morphine, and no response at all to the antidepressants desipramine and reboxetine. The authors concluded that Gz mediates the effects of specific receptors, defining a unique role for Gzalpha in platelets and the in the central nervous system. The importance of this work is that it shows that receptors interact selectively with G proteins, and that G protein subunits are not interchangeable. The importance of this work for drug abuse research is that it implicates the Gzalpha protein in the signaling pathways induced by cocaine and morphine, opening the way for further research on this part of the signal transduction cascade. Yang, J., et al. Loss of Signaling Through the G Protein, Gz, Results in Abnormal Platelet Activation and Altered Responses to Psychoactive Drugs. Proc. Natl. Acad. Sci. USA, 97, pp. 9984-9989, 2000.
Vesicle Transporters Regulate Neurotransmitter Release by Two Mechanisms
The vesicle monoamine transporter (VMAT2) is responsible for the uptake of monoamine neurotransmitters (such as dopamine) into synaptic vesicles. Amphetamines act by reversing the action of VMAT2. NIDA grantees Drs. Sulzer and Edwards and their co-workers found that overexpression of VMAT2 in small synaptic vesicles in cultured neurons led to an increase in the number of vesicles released per event (quantal size) and in the frequency of release. This is an unexpected result because transporters were not thought to be rate-limiting in vesicle accumulation. In light of these findings, it is clear that the regulation of vesicle transporter activity leads to rapid and profound changes in transmitter release. The result is a profound increase of released neurotransmitter to multiple post-synaptic sites and a resultant synaptic strengthening. The importance of this paper is that it points out an important regulatory role for VMAT2, a protein that is a target for amphetamine. Pothos, E.N., et al. Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size. J. Neurosci., 20, pp. 7297-7306, 2000.
Modulation of Morphine-Induced Antinociception by Glucose
The analgesic potency of opioid drugs varies as a function of gender, and can be modified by the intake of palatable sweet-tasting solutions. Male and female Long-Evans rats were fed laboratory chow and water alone, or chow, water and either a 32% sucrose solution or a 0.15% saccharin solution. Following the administration of cumulative doses of morphine sulfate, the rats were tested in two analgesic paradigms, the tail-flick test and the hot-plate test. On the tail-flick test, morphine produced dose-related increases in antinociceptive responses. Chronic sucrose intake significantly augmented morphine's antinociceptive properties. On the hot-plate test, when the plate was heated to 51¼ C, morphine led to significant dose-related increases in antinociceptive responses, irrespective of sucrose intake. However, when the temperature of the hot plate was increased to 53¼ C, there was a trend for animals given sucrose to display greater antinociceptive responses. No differences in baseline pain sensitivity or morphine-induced analgesia were observed as a function of gender. Kanarek, R.B., Homoleski, B. Modulation of Morphine-Induced Antinociception by Palatable Solutions in Male and Female Rats. Pharmacology Biochemistry and Behavior, 66, pp. 653-659, 2000.
Heterodimerization of Mu and Delta Opioid Receptors: A Role in Opiate Synergy
Opiate analgesics are widely used in the treatment of severe pain. Three opioid-receptor types, delta, kappa and mu, have been identified. Pharmacological studies have suggested that mu and delta receptors interact and influence each other's properties. While most opiates exert their analgesic effects primarily via mu opioid receptors, delta receptor selective drugs have been shown to enhance their potency. The molecular basis for these findings has not been previously elucidated. NIDA grantees Lakshmi Devi and her coworkers have recently found that co-expression of mu and delta receptors in heterologous cells followed by selective immunoprecipitation results in the isolation of mu-delta heterodimers. Treatment of these cells with extremely low doses of certain delta selective ligands results in a significant increase in the binding of a mu receptor agonist. Similarly, treatment with mu selective ligands results in a significant increase in the binding of a delta receptor agonist. This robust increase is also seen in SK-N-SH cells that endogenously express both mu and delta receptors. Furthermore, we find that a delta receptor antagonist enhances both the potency and efficacy of the mu receptor signaling; likewise a mu antagonist enhances the potency and efficacy of the delta receptor signaling. A combination of agonists (mu and delta receptor selective) also synergistically binds and potentiates signaling by activating the mu-delta heterodimer. Taken together, these studies show that heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have important clinical ramifications and may provide new foundations for more effective therapies. Gomes, I., Jordan, B.A., Gupta, A., Trapaidze, N., Nagy, V., and Devi, L.A. Heterodimerization of Mu and Delta Opioid Receptors: A Role in Opiate Synergy. J. Neuroscience, 20, RC110: 1-5, 2000.
Morphine Induces Gene Expression in Human Lymphocytes
Opiate users constitute a large portion of the patient population contracting AIDS. The feasibility and success of human studies have always been hampered by the complexity of an individual's history of i.v. drug use. Thus, rhesus monkeys treated with opioids and infected with simian immunodeficiency virus (SIV) provide an excellent animal model for studying drug abuse and AIDS in a controlled manner. All HIV-1 strains studied to date use CCR5, CXCR4, or both receptors to enter cells. Research on several genetically divergent SIV isolates has revealed that SIV uses CCR5, and not CXCR4, for entry. CEM x174, a human lymphoid cell line, has been routinely used to cultivate and maintain various SIV strains. However, questions have arisen about how CEM x174, which reportedly was unable to express detectable amounts of CCR5 transcripts, efficiently supports the growth of SIV. Using a sensitive, competitive RT-PCR procedure, Dr. Ronald Y. Chuang and his colleagues at the University of California, Davis attempted to detect as well as quantify the amount of CCR5 expression. Their findings indicate that: (1) CEM x174 expresses CCR5; and (2) the amount of CCR5 is increased in cells pre-treated with morphine. These results correlate well with their previous observations that morphine treatment causes CEM x174 cells to be more susceptible to SIV-infection. Similar morphine effects were not observed on CEM x174 cells infected with SRV (simian retroviruses) that do not depend on CCR5 for entry. These findings suggest a plausible mechanism whereby opiate drug users render themselves more susceptible to HIV infection. These data contributing substantially to explaining the vast prevalence of HIV infection among endemic drug use populations. Miyagi, T., Chuang, L.F., Doi, R.H., Carlos, M.P., Torres, J.V. and Chuang, R.Y. Morphine Induces Gene Expression of CCR5 in Human CEMx174 Lymphocytes. J. Biol. Chem., 275, pp. 31305-31310, 2000.
Phosphorylation and Sequestration of Serotonin Transporters Differentially Modulated by Psychostimulants
Many psychotropic drugs interfere with the re-uptake of dopamine, norepinephrine and serotonin. The actions of serotonin are terminated by active transport. Whereas serotonin actions are mediated by more than 15 different types of receptors, a single serotonin transporter is responsible for extracellular serotonin clearance. NIDA grantee Randy D. Blakely and his coworkers at the Vanderbilt University School of Medicine have recently investigated whether the regulation of serotonin transporters was influenced by transport per se and whether serotonin transporter ligands differentially influenced serotonin transporter regulation. Transport capacity is regulated by kinase-linked pathways, particularly involving protein kinase C, leading to transporter phosphorylation and sequestration. Phosphorylation and sequestration of the serotonin transporter were significantly impacted by ligand occupancy. Ligands that can permeate the transporter, such as serotonin or the amphetamines, prevented protein kinase C-dependent serotonin transporter phosphorylation. Non-transported serotonin transporter antagonists such as cocaine and antidepressants were permissive for serotonin transporter phosphorylation. Protein kinase C-dependent serotonin transporter sequestration was also blocked by serotonin. These findings reveal activity-dependent modulation of neurotransmitter reuptake and identify novel consequences of amphetamine and cocaine action. Ramamoorthy, S. and Blakely, R.D. Phosphorylation and Sequestration of Serotonin Transporters Differentially Modulated by Psychostimulants. Science, 285(5428), pp. 763-766, 1999.
Characterization and Analysis of Biphalin - An Opioid Peptide with a Palindromic Sequence
In this study Dr. Hettiarachchi and his colleagues characterized and analyzed a structurally modified opioid peptide, biphalin, when standard techniques for peptide analysis were inadequate. Biphalin, an octapeptide consisting of two monomers of a modified enkephalin, attached via a hydrazine bridge, and with the amino acids assembled in a palindromic sequence, needed strict quality control because of certain drawbacks associated with its synthesis. Many techniques were used for its analysis including elemental analysis, amino acid analysis, amino acid sequence analysis (AASA), mass spectrometry (MS), 1H-NMR, 1H-correlated spectroscopy (COSY)-NMR, high performance liquid chromatography (HPLC), and capillary electrophoresis (CE). Electrospray ionization (ESI) mass spectrometry that included both ESI MS and ESI MS/MS, was performed to confirm the full sequence since AASA results alone could verify only the monomer sequence and not the full sequence. Although the 1H-NMR results led to a preliminary assignment of many protons, the 1H COSY-NMR results allowed for an unequivocal assignment of almost all protons. The peptide purity was determined by reversed phase HPLC and CE. Hettiarachchi, K., Ridge, S., Thomas, D.W., Olson, L., Obi, C.R., and Singh, D. Characterization and Analysis of Biphalin - An Opioid Peptide With A Palindromic Sequence, J. Peptide Research, 57, 1-12 (2001), 2000.
Dopamine and cAMP-Regulated Phosphorylation
Dr. Paul Greengard, one of the winners of the 2000 Nobel Prize in Medicine and Physiology, has been characterizing the actions of dopamine and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32). DARPP-32 is a central player in mediating the actions of dopamine by regulating the amount of phosphorylation of proteins in spiny neurons of the striatum where dopamine receptors are localized. When DARPP-32 is phosphorylated it inhibits protein-phosphatase, an enzyme that decreases the amount of phosphorylation and, at the same time, augments the action of neurotransmitters that increase phosphorylation. Mice lacking the DARPP-32 gene show a reduced behavioral response to drugs of abuse such as cocaine and D-amphetamine.
In a recent paper, Dr. Greengard's group shows that mice lacking DARPP32 do not display long-term potentiation or long-term depression in synapses connecting the striatum to the cortex. These results are similar to those produced by blocking the dopamine D1 receptor. However, they report that distinct biochemical pathways seem to play a significant role in mediating the two forms of synaptic plasticity. Blockade of protein kinase A blocks the induction of long-term potentiation but not long-term depression while blockade of protein kinase G pathway blocks long-term depression and not long-term depression at corticostriatal synapses. These forms of plasticity may play an important role in addiction in term of habit formation and impulse control. Through understanding the biochemical pathways that control these forms of plasticity, researchers hope to develop new and more effective treatment interventions. Calabresi, P., Gubellini, P., Centonze, D., Picconi, B., Bernardi, G., Chergui, K., Svenningsson, P., Fienberg, A.A., and Greengard, P. Dopamine and cAMP-Regulated Phosphoprotein 32 kDa Controls Both Striatal Long-Term Depression and Long-Term Potentiation, Opposing Forms of Synaptic Plasticity. J. Neurosci.20(22), pp. 8443-8451, 2000.
Agmatine and Pain Control in Mammals
Dr. Carolyn Fairbanks and Dr. George Wilcox of the University of Minnesota examined the analgesic properties of agmatine. Agmatine, an amine known to exist in bacteria, plants, and invertebrates, has recently been found in the central nervous system (CNS) of mammals. Agmatine appears to function as a neurotransmitter/ neuromodulator within the CNS, where its activity includes the antagonism of NMDA receptors and the inhibition of nitric oxide synthase (NOS). The activation of both NMDA receptors and of the NOS have been implicated in plastic changes of the CNS responsible for chronic pain. Drs. Fairbanks and Wilcox have found that intrathecal administration of agmatine in rodents decreased chronic pain associated with inflammation and nerve injury, but did not alter normal acute pain perception. These analgesic actions were not associated with motor impairment, a common side effect of NMDA antagonists. This research suggests that agmatine may be an effective alternative to opioids in the treatment of chronic pain Fairbanks et al., Agmatine Reverses Pain Induced by Inflammation, Neuropathy, and Spinal Cord Injury. Proc. Natl. Acad. Sci., 97(19), pp. 10584-10589, 2000.
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