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Allan I Basbaum

Publications and source records attributed to Allan I Basbaum.

33 records · Page 2Linked to original sources
PubMed2003

Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis.

Mouse genetics has contributed significantly to our understanding of molecular mechanisms underlying tissue and nerve injury-induced persistent pain. To create a highly reproducible, relatively noninvasive model of neuropathic pain in the mouse, we examined the behavioral consequences of sparing each of the 3 distal branches of the sciatic nerve in wild-type mice after a model originally described in the rat. Sparing the tibial branch but sparing neither of the other branches produced robust mechanical allodynia while leaving heat sensibility intact. To assess the topographic organization of the IB4 population of afferents from each branch and to compare anatomic consistency across injury models, we examined loss of thiamine monophosphatase staining in the superficial dorsal horn after peripheral nerve injury. We found that each of the sciatic branches targets a distinct mediolateral location in inner lamina II and that each of the spared nerve injury models produced a more reproducible pattern of thiamine monophosphatase staining loss than did partial tight ligation. These results improve on previous nerve injury models in mouse, demonstrate similar behavioral changes as in rat, and provide novel information on the topographic organization of small diameter peripheral afferents in the mouse spinal cord.

Animals↗
PubMed2003

Preprotachykinin-A gene deletion protects mice against acute pancreatitis and associated lung injury.

Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Preprotachykinin-A (PPT-A) gene products substance P and neurokinin (NK)-A have been shown to play important roles in neurogenic inflammation. Substance P acts primarily (but not exclusively) via the NK1 receptor. NKA acts primarily via the NK2 receptor. Earlier work has shown that knockout mice deficient in NK1 receptors are protected against acute pancreatitis and associated lung injury. NK1 receptors, however, bind other peptides in addition to substance P, not all of which are derived from the PPT-A gene. To examine the role of PPT-A gene products in acute pancreatitis, the effect of PPT-A gene deletion on the severity of acute pancreatitis and the associated lung injury was investigated. Deletion of PPT-A almost completely protected against acute pancreatitis-associated lung injury, with a partial protection against local pancreatic damage. These results show that PPT-A gene products are critical proinflammatory mediators in acute pancreatitis and the associated lung injury.

Acute Disease↗
PubMed2002

Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences.

The analgesia produced by inhibitory G protein-coupled receptor agonists involves coordinated postsynaptic inhibition via G protein-coupled inwardly rectifying potassium channels (GIRKs) and presynaptic inhibition of neurotransmitter release through regulation of voltage-gated Ca(2+) channels. Here, we used mice lacking the GIRK2 channel subunit to assess the relative contribution of these two effector systems to nociceptive processing in male and female mice. Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid (morphine) and alpha(2)-adrenergic (clonidine) receptor-induced antinociception in a spinal reflex test. The GIRK2-null mutation reduced the "pain" threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold. In addition, deletion of GIRK2 channels in mutant mice largely eliminated clonidine antinociception and significantly decreased morphine antinociception. Furthermore, the more pronounced morphine and clonidine-induced antinociception in male mice disappeared in the GIRK2 mutants. Based on the almost complete loss of clonidine-induced antinociception in the mutant mice, we conclude that it is primarily mediated by postsynaptic alpha(2)-adrenergic receptors. In contrast, the significant residual morphine effect in the mutant mice points to the presynaptic mu opioid receptor as a major contributor to its analgesic action. Finally, our results suggest that the reduced pain responsiveness of male compared with female mice results in part from GIRK2-coupled postsynaptic receptors that are activated by endogenous antinociceptive systems.

Adrenergic alpha-Agonists↗
PubMed2002

Transneuronal tracing of diverse CNS circuits by Cre-mediated induction of wheat germ agglutinin in transgenic mice.

Systems neuroscience addresses the complex circuits made by populations of neurons in the CNS and the cooperative function of these neurons. Improved approaches to the neuroanatomical analysis of CNS circuits are thus of great interest. In fact, significant advances in tract-tracing methods have recently been made by using transgenic mice that express transneuronal lectin tracers under the control of neuron-specific promoters. The utility of those animals, however, is limited to the CNS circuit influenced by the particular promoter. Here, we describe a new transgenic mouse that can be used for transneuronal tracing analysis of circuits in any region of the brain or spinal cord. The transgene in these mice results in expression of LacZ in neurons throughout the CNS. Excision of the LacZ gene by Cre-mediated recombination initiates expression of the lectin, wheat germ agglutinin (WGA). To illustrate the diverse uses of these ZW (LacZ-WGA) mice, we triggered WGA expression either by crossing the mice with two Cre-expressing transgenic mouse lines or by microinjecting a Cre-expressing adeno-associated virus into the cerebellum or cerebral cortex. Both approaches resulted in extensive WGA expression in the cell bodies and dendrites of neurons in which the recombination event occurred, as well as anterograde and transneuronal transport of the lectin to second and third order neurons. Because the lectin can be induced in developing and adult animals, and in all regions of the brain and spinal cord, these ZW may prove extremely valuable for numerous studies of CNS circuit analysis.

Animals↗
PubMed2002

Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation.

The peripheral branch of primary sensory neurons regenerates after injury, but there is no regeneration when their central branch is severed by spinal cord injury. Here we show that microinjection of a membrane-permeable analog of cAMP in lumbar dorsal root ganglia markedly increases the regeneration of injured central sensory branches. The injured axons regrow into the spinal cord lesion, often traversing the injury site. This result mimics the effect of a conditioning peripheral nerve lesion. We also demonstrate that sensory neurons exposed to cAMP in vivo, when subsequently cultured in vitro, show enhanced growth of neurites and an ability to overcome inhibition by CNS myelin. Thus, stimulating cAMP signaling increases the intrinsic growth capacity of injured sensory axons. This approach may be useful in promoting regeneration after spinal cord injury.

Animals↗
PubMed2002

Mu and delta opioid receptor-like immunoreactivity in the cervical spinal cord of the rat after dorsal rhizotomy or neonatal capsaicin: an analysis of pre- and postsynaptic receptor distributions.

Opioid compounds have powerful analgesic properties when administered to the spinal cord. These effects are exerted through mu and delta opioid receptors, and both pre- and postsynaptic mechanisms have been implicated. To specifically address the relative pre- and postsynaptic contribution to spinal opioid analgesia, we have quantitatively assessed the pre- vs. postsynaptic distribution of the mu-opioid (MOR-1, MOP(1)) and delta-opioid receptors (DOR-1, DOP(1)). We also examined the rostro-caudal arborization of MOR-1 and DOR-1 immunoreactive primary sensory neurons, using an isolated dorsal root preparation. These results were compared to those obtained by labeling for calcitonin gene-related peptide (CGRP), a neuropeptide whose expression in the spinal cord is restricted to the terminals of small diameter primary sensory neurons. We estimate that approximately one half of MOR-1 and two thirds of DOR-1 immunoreactivity in the cervical spinal cord is located on primary afferent fibers. These fibers have a broad rostro-caudal distribution, extending at least three segments rostral and caudal to their segment of entry. Regardless of marker used, the rostral projection was greatest, however, the distribution of CGRP-immunoreactive fibers differed somewhat in that they had a much smaller projection to the most caudal segments examined. Our results suggest that presynaptic delta opioid actions predominate, but that there are mixed pre- and postsynaptic inhibitory effects exerted by opioid analgesics that act at the spinal cord mu opioid receptor.

Animals↗
PubMed2002

The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors.

Serotonin is a major component of the inflammatory chemical milieu and contributes to the pain of tissue injury via an action on multiple receptor subtypes. Here we studied mice after genetic or pharmacological disruption of the 5-HT(3) receptor, an excitatory serotonin-gated ion channel. We demonstrate that tissue injury-induced persistent, but not acute, nociception is significantly reduced after functional elimination of this receptor subtype. Specifically, in the setting of tissue injury, the 5-HT(3) receptor mediates activation of nociceptors but does not contribute to injury-associated edema. This result is explained by the localization of 5-HT(3) receptor transcripts to a previously uncharacterized subset of myelinated and unmyelinated afferents, few of which express the proinflammatory neuropeptide substance P. Finally, we provide evidence that central serotonergic circuits modulate nociceptive transmission via a facilitatory action at spinal 5-HT(3) receptors. We conclude that activation of both peripheral and central 5-HT(3) receptors is pronociceptive and that the contribution of peripheral 5-HT(3) receptors involves a novel complement of primary afferent nociceptors.

Animals↗
PubMed2002

Long-term deprivation of substance P in PPT-A mutant mice alters the anoxic response of the isolated respiratory network.

The aim of this study was to elucidate the role of the neuromodulator substance P and its related tachykinin neurokinin A (NKA) in the homeostasis of respiratory activity. Respiratory activities, in form of fictive eupneic and sigh activities, were recorded extracellularly from the preBötzinger complex (PBC) in normoxic and anoxic conditions using medullary slice preparations. The effect of a blockade of endogenous substance P was assessed by an acute pharmacological blockade of the receptors with spantide in wild-type animals and by the use of preprotachykinin-A (PPT-A) mutants. These mutants lack from birth the PPT-A gene, which codes for the precursor of substance P and NKA. Spantide treatment reduced frequency (-37%, n = 9) and regularity (twofold) of eupneic-like respiratory activity under normoxic conditions, whereas in PPT-A mutants, eupneic-like activity was under normoxic conditions not significantly different from the wild-type mice (WT). The response to short anoxic episodes (5 min) was characterized in the WT by an increase in respiratory frequencies at the onset of anoxia (ratio anoxic/control frequency = 1.9 +/- 0.2, n = 18). This anoxic ratio was unaltered in the presence of spantide (ratio = 2.3 +/- 0.4, n = 8) but increased in the mutant (ratio = 4.1, n = 15). We conclude that endogenously released substance P is important for the maintenance of regular respiratory activity. Short-term blockade of substance P receptors decreases the frequency and regularity of rhythmic activity. Long-term deficiency in substance P leads to compensatory mechanisms that result in an apparently normal respiratory activity under normoxic conditions but a significantly altered response of the respiratory network during anoxia.

Animals↗
PubMed2001

Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKC gamma mutant mice.

A variety of second messenger systems have been implicated in the intracellular mechanisms of tolerance development to the analgesic actions of morphine, a mu opioid, and clonidine, an alpha-2 adrenergic receptor agonist. Here, we studied mice that carry a null mutation in the gene encoding a neuronal specific isoform of protein kinase C (PKC), namely, PKC gamma. We used the tail-flick test to construct dose-response curves before and 4 days after chronic morphine (75-mg pellets, subcutaneously (s.c.)) or clonidine treatment (0.3mg/kg, s.c., twice daily). Baseline tail-flick latencies did not differ in PKC gamma mutant and wild-type mice (3-4s). Both morphine and clonidine produced a dose-dependent suppression of the tail-flick response with an ED(50) (effective dose resulting in a 50% reduction of the control response) value (2.0mg/kg for morphine and 0.1mg/kg for clonidine) that was similar for naive mutant and wild-type mice. In contrast, after 4 days of drug delivery, mutant mice showed significantly less rightward shift in the dose-response curve to morphine (six-fold for wild-type and three-fold for mutant mice) and to clonidine (five-fold for wild-type and no shift for the mutant mice). These results indicate that PKC gamma contributes to the development of tolerance to the analgesic effects of both morphine and clonidine. Chronic morphine treatment can also result in sensitization of spinal cord neurons and increased pain behaviors following a noxious insult. To assess the contribution of PKC gamma to this process, we studied the responses of wild-type and mutant mice to an intraplantar injection of formalin (a model of persistent pain) following chronic morphine treatment. Although morphine tolerance increased formalin-evoked persistent pain behavior and Fos-LI in wild-type mice, there was no difference between placebo- and morphine-treated mutant mice, suggesting that PKC gamma also contributes to chronic morphine-induced changes in nociceptive processing.

Analgesics↗
PubMed1999

Spinal cannabinoids are anti-allodynic in rats with persistent inflammation.

Cannabinoid receptor (CB1) agonists strongly inhibit behavioral responses to acute noxious stimuli, but their effects on behavioral responses in persistent pain states are less clear. Here, we examined the effects of intrathecal (i.t.) administration of a CB1 agonist, WIN55,212-2, on mechanical allodynia (decreased withdrawal threshold) produced by injections of complete Freund's adjuvant (CFA) in the plantar surface of the rat hindpaw. We measured mechanical thresholds with calibrated von Frey filaments before and after CFA and used Fos expression as a marker of the activity of spinal cord neurons during inflammation and in response to a CB1 antagonist. One day post CFA-induced injury, mechanical sensitivity was significantly increased in the hindpaw ipsilateral to the CFA injection, as was the number of neurons that express Fos. Intrathecal injection of WIN55,212-2, significantly, reversed the allodynia at doses that had no effect on the mechanical threshold of the contralateral paw of CFA-treated or the withdrawal thresholds in naive animals. This effect was blocked by coadministration of the CB1 antagonist, SR141716A, with WIN55212-2. By itself, SR141716A, had no effect on mechanical thresholds in normal animals. In inflamed animals, SR141716A did not further reduce mechanical thresholds in the inflamed paw, but it significantly enhanced mechanical sensitivity 'contralateral' to the inflammation. Furthermore, i.t. injection of SR141716A increased Fos expression in both normal and inflamed animals, to a different extent in different laminae. In normal animals, the increase was primarily in laminae V-VI and in the ventral horn; in animals with persistent inflammation SR141716A increased the number of Fos neurons in laminae I-II and V-VI. These results demonstrate that WIN55212-2 reverses inflammation-induced allodynia at doses that do not produce analgesia and that SR141716A differentially affects the pattern of Fos expression in the spinal cord, depending on the presence or absence of inflammation. Taken together, these results suggest that the CB1 receptor system is tonically active in the spinal cord under normal conditions and that its activity is increased in response to injury.

Analgesics↗
PubMed1999

Second messengers, the substantia gelatinosa and injury-induced persistent pain.

Although there is now unequivocal evidence that the circuitry within the substantia gelatinosa is a major contributor to the transmission and control of nociceptive messages, this was not known 35 years ago, when Pat Wall first focussed attention on this region. In addition to being the target of neurochemically distinct nociceptors, this region contains a heterogeneous population of excitatory and inhibitory interneurons. This review focuses on the contribution of second messenger systems that are found in the substantia gelatinosa. In particular the review highlights their critical contribution to the development of persistent pain conditions in the setting of tissue and nerve injury. Several of the studies used animals with deletions of genes that encode major second messenger molecules, including protein kinase A, C and nitric oxide synthase. Our laboratory has shown that mice with a deletion of the gene that encodes the gamma isoform of protein kinase C (which is almost exclusively expressed in a population of interneurons of the inner part of the substantia gelatinosa) have completely normal acute pain responses. However, the allodynia that characteristically develops after injury does not occur in these mice, particularly when it is generated by partial sciatic nerve injury. By contrast, deletion of genes that encode protein kinase A subunits only show deficits in the development of tissue inflammation-induced pain. These differences highlight the selectivity that characterizes the contribution of different second messenger molecules. Because of the restricted distribution of these molecules, it is likely that they are activated by different populations of primary afferent nociceptor and under very different conditions of injury. Understanding the circuitry within the substantia gelatinosa is thus critical to elucidating the mechanisms through which these second messenger molecules contribute to the development of persistent pain in the setting of injury.

Animals↗
PubMed1995

The development of opioid tolerance in the formalin test in the rat.

The formalin test produces persistent pain in animals and is believed to provide a better model of the pain experienced by humans than do tests that measure reflex nociceptive thresholds. The present study evaluated whether tolerance to morphine develops in the formalin test in the rat. Morphine (75 mg) or vehicle pellets were implanted subcutaneously for 5 consecutive days. On the 6th day, a subcutaneous (s.c.) dose of either morphine (10 mg/kg) or saline was given 30 min prior to the injection of 50 microliters of 5% formalin into the left hindpaw of the rats. In vehicle-pelleted rats administered saline, formalin evoked characteristic pain behavior consisting of licking, biting and flinching of the affected hindpaw. The pain behavior in morphine-tolerant rats given morphine did not differ significantly from the saline control; i.e., tolerance to the analgesic effect of morphine was demonstrable in the formalin test. These results do not agree with previous published reports. Rather, these results suggest that the mechanisms involved in morphine analgesia in the formalin test and in reflex nociceptive tests are similar and subject to the same problem of tolerance with chronic opioid administration.

Analgesics, Opioid↗
PubMed1992

Do opioids evoke the release of serotonin in the spinal cord? An in vivo microdialysis study of the regulation of extracellular serotonin in the rat.

This study investigated the regulation of serotonin (5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal spinal cord of awake, freely moving rats, using microdialysis coupled to HPLC with electrochemical detection and tested the hypothesis that opioids exert their analgesic effect in part through the increased release of 5-HT in the dorsal horn. A dialysis tube was placed transversely at the L4 segment of the dorsal spinal cord and the basal concentration of 5-HT in the dialysate was characterized by infusion of a variety of substances through the dialysis probe: tetrodotoxin (TTX), KCl, imipramine, fluoxetine and amphetamine (AMPH). To evaluate the contribution of opioids, we also studied the effects of either systemic or intracerebroventricular (i.c.v.) injection of morphine or DAMGO. Extracellular concentrations of 5-HT and 5-HIAA were partially and reversibly reduced by TTX. In the presence of KCl, imipramine, fluoxetine or AMPH, 5-HT levels significantly increased. Under these conditions, extracellular 5-HIAA levels usually decreased. By contrast, the effects of opioids on 5-HT concentrations were highly variable. Low doses of morphine administered systemically increased 5-HT concentrations in only 3 of 6 rats. This was paralleled by a decrease in 5-HIAA. Higher doses of morphine, alone or in the presence of fluoxetine, did not change 5-HT concentrations. Intracerebroventricular injection of morphine or DAMGO increased the extracellular concentrations of 5-HT in only about one third of the animals. After intracerebroventricular opioid injection, extracellular concentrations of 5-HIAA either decreased by about 20% or did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1977

Reversal of morphine and stimulus-produced analgesia by subtotal spinal cord lesions.

This study examined the hypothesis that descending inhibitory pathways from brain stem to spinal cord mediate the analgesic effect of both electrical brain stimulation and morphine. In the first set of experiments, the effect of subtotal midthoracic spinal cord lesions on the analgesic effect of electrical stimulation in the periaqueductal gray matter of the rat was examined. In the second, the effect of similar cord lesions on the analgesic effect of intraperitoneal morphine was studied. In both cases, a lesion of the dorsal part of the lateral funiculus (DLF) reduced or abolished the analgesia of the hindlimbs. Analgesia of the forelimbs was unaffected. Lesions of the dorsal columns, which include the corticospinal tract, or lesions of the ventral part of the lateral funiculus had no effect on analgesia. It is concluded that an inhibitory pathway, which descends in the dorsal part of the lateral funiculus and which probably originates in the nucleus raphe magnus of the medulla, mediates the descending control found in both morphine and stimulus-produced analgesia.

Analgesia↗