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Biomedical subjects

A I Basbaum

Publications and source records attributed to A I Basbaum.

At least 91 records · Page 5Linked to original sources
PubMed1994

Walking evokes a distinctive pattern of Fos-like immunoreactivity in the caudal brainstem and spinal cord of the rat.

We have evaluated the pattern of c-fos expression induced in the rat spinal cord, caudal brainstem and cerebellum by a behavior that is associated with non-noxious inputs transmitted over large-diameter primary afferent fibers, namely walking for 1 h on a rotating rod. Walking on the rotating rod induced a large increase in the number of Fos-like immunoreactive neurons in regions of the cervical and lumbar spinal cord gray matter that contain neurons that respond to non-noxious stimuli: the inner part of the substantia gelatinosa (lamina IIi), the nucleus proprius and the medial parts of laminae V and VI. We also observed considerable labeling in lamina VII and in ventral horn motoneurons. We did not record an increased number of Fos-like immunoreactive neurons in lamina I, in the outer substantia gelatinosa (lamina IIo), or in the lateral, reticulated portion of lamina V, regions that contain neurons predominantly responsive to noxious stimulation. Unilateral sensory deafferentation of the forelimb, by multiple dorsal rhizotomies, significantly decreased the number of Fos-like immunoreactive neurons in the ipsilateral spinal cord, suggesting that afferent input contributed to the walking-induced pattern of labeling. In rats that walked on the Rota-Rod, we also recorded increased labeling in the dorsal column nuclei. Unilateral cervical deafferentation reduced the labeling in the cuneate nucleus; this reduction was paralleled by decreased cytochrome oxidase activity. Finally, we found that there was a significant increase in the number of Fos-like immunoreactive neurons in the cerebellum of rats that walked on the Rota-Rod. Northern blot analysis revealed that the increase in Fos-like immunoreactivity was associated with an increase in c-fos messenger RNA. The pattern of labeling observed in the rats that walked on the Rota-Rod was distinct from that observed when rats are exposed to a noxious stimulus [Presley et al. (1990) J. Neurosci. 10, 323-335]. This result reinforces the conclusion that by monitoring the evoked expression of the c-fos proto-oncogene, it is possible to identify unique populations of neurons that are specifically related to the modality of the stimulus or to behaviour occurring during the stimulus presentation.

Animals↗
PubMed1994

Role of vagal afferents and spinal pathways modulating inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine.

1. Nicotine, a major active component of tobacco smoke, has been shown to modulate the inflammatory response via both peripheral and central nervous system pathways. Recently we found that spinal intrathecal administration of nicotine dose-dependently inhibits bradykinin-induced plasma extravasation (BK-induced PE) in the knee joint of the rat and that the dose-response curve for the inhibition of BK-induced PE by intrathecal nicotine is shifted to the left, by six orders of magnitude, after surgical interventions in the abdominal cavity, which might have interrupted visceral afferents to the neuraxis. Therefore we focused, in this study, on the contribution of the vagal afferents to depression of BK-induced PE by intrathecal nicotine. Furthermore, the effect of acute spinalization at the level C6-C8 was investigated. The hypothesis was that impulse activity in vagal afferents has a pronounced inhibitory effect on the modulation of BK-induced PE by intrathecal nicotine and that spinal pathways are important in mediating this effect. 2. Chronic subdiaphragmatic vagotomy and elimination of vagal afferents, by neonatal capsaicin treatment or by application of kainic acid to the nodose ganglia, enhanced the potency of intrathecal nicotine depression of BK-induced PE, by six to seven orders of magnitude when compared with the control. 3. Acute subdiaphragmatic vagotomy enhanced the potency of intrathecal nicotine-induced depression of BK-induced PE (without changing its maximum effect), by about three to four orders of magnitude when compared with the sham-operated (control) animals (with intact vagus nerves).(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1994

Differential effects of morphine on noxious stimulus-evoked fos-like immunoreactivity in subpopulations of spinoparabrachial neurons.

In previous studies we reported that although morphine dose dependently inhibits noxious stimulus-evoked expression of the c-fos proto-oncogene in the rat spinal cord, morphine was without effect in certain populations of presumed nociresponsive neurons, even under conditions of complete behavioral analgesia. To determine whether the neurons that continue to express the c-fos gene include projection neurons, we evaluated the effect of morphine on noxious stimulus-evoked c-fos expression in spinoparabrachial neurons retrogradely labeled with Fluoro-gold. In the formalin test, we found that morphine analgesia was associated with a significant reduction in the number of Fos-like-immunoreactive spinoparabrachial projection neurons in the lateral reticulated area of the neck of the dorsal horn. Morphine, however, did not reduce the number of Fos-like-immunoreactive spinoparabrachial projection neurons either in the superficial dorsal horn or in the area around the central canal. These results indicate that under conditions of morphine analgesia two distinct populations of spinoparabrachial neurons can be recognized on the basis of their expression of the c-fos gene in response to noxious stimulation. Since the expression of the c-fos gene has been correlated with neuronal activity, these data suggest that activity, and central transmission of nociceptive information, persists in certain nociresponsive projection neurons during morphine analgesia. Alternatively, if activity has, in fact, been blocked in these neurons, our results indicate that injury can produce significant molecular changes in neurons even though the neuronal activity and pain associated with the injury is blocked by morphine.

Animals↗
PubMed1994

Transneuronal spread of the pseudorabies virus after injection into the central nucleus of the amygdala in the rat.

The pseudorabies virus (PRV) is a swine alpha herpes virus that is widely used as a neural tracer because of its marked neurotropism and transneuronal transmissibility (Card et al., 1991, 1992; Strack and Loewy 1990). PRV has been used to retrogradely identify spinal cord and brainstem connections to various peripheral organs, but few anatomical studies have used CNS inoculation of PRV to investigate intrinsic brain connectivity. Improved knowledge of the mode and temporal pattern of transneuronal spread is essential for interpretation of PRV tracing studies, and is also a prerequisite to the use of this and other herpes viruses as vectors in the CNS. This study investigated the distribution of PRV labelling in the CNS at various time points after its injection into the central nucleus of the amygdala (CA). The results indicate that detection of PRV in a retrogradely labelled site at any given time after injection is not only a function of the number of synapses in the pathway from the injection site, but is also highly dependent on the axon lengths involved, much more than would be expected if fast axonal transport were the limiting factor. In addition, the window of time during which PRV may be detected in a given site is limited ultimately by neuronal destruction.

Amygdala↗
PubMed1993

Effects of injury discharge on the persistent expression of spinal cord fos-like immunoreactivity produced by sciatic nerve transection in the rat.

We recently reported that peripheral nerve injury produced by sciatic nerve transection induces a persistent increase in the expression of the immunoreactive Fos protein product of the c-fos proto-oncogene, an indicator of neuronal activity, in the lumbar spinal cord of the rat and that local anesthetic blockade of the peripheral neuroma attenuates this long-term expression of Fos. In addition to the sustained activity of the injured afferents, the nerve transection itself results, acutely, in a massive injury-induced neural discharge. In this study we evaluated the effect of blocking this massive injury discharge on the persistence of Fos expression. Just prior to nerve transection we applied the short-acting local anesthetic, lidocaine, to the sciatic nerve. Control injections were made subcutaneously on the dorsum of the neck. We report that injection of the local anesthetic, by either route, significantly reduced the number of fos-like immunoreactive neurons at 2 days after nerve transection. The effect was only observed on neurons in the superficial dorsal horn. These results indicate that along with sustained activity of injured afferents and of reorganization of central circuits after injury, the initial brief discharge at the time of nerve injury contributes to a prolonged increase in the activity of spinal cord neurons.

Animals↗
PubMed1993

Peripheral and central contributions to the persistent expression of spinal cord fos-like immunoreactivity produced by sciatic nerve transection in the rat.

Previous studies have demonstrated that noxious stimuli, intense enough to produce tissue injury, evoke a transient expression of the Fos protein product of the c-fos proto-oncogene in neurons, in regions of the spinal cord that contribute to the transmission of nociceptive messages in the rat. Since there is evidence that increases in fos-like immunoreactivity reflect increases in neuronal activity, it has thus been possible to identify populations of neurons that are activated in response to tissue injury. In this study we used immunocytochemical localization of fos-like immunoreactive (FLI) neurons to map the patterns of neuronal activity in the spinal cord at different times after peripheral nerve injury in the rat. Sciatic nerve transection induced a persistent (at least 1 month) elevation in the number of FLI neurons, predominantly in laminae 1, 2, 5, 6 and 7 of the ipsilateral lumbar enlargement of the spinal cord. In the L5 segment, the expression of fos-like immunoreactivity in the superficial dorsal horn (laminae 1 and 2) fluctuated, with peaks of Fos expression at 2 h, 2 days and 2 weeks after nerve transection. Furthermore, by 2 weeks after nerve injury, the distribution of labelled neurons in the superficial laminae of the dorsal horn shifted, with the most densely labelled cells now located in the central portion of the superficial dorsal horn. In contrast, the pattern of labelled neurons in laminae 5, 6 and 7 was relatively constant over the 4-week study period. Local anesthetic block of the sciatic nerve significantly decreased the number of FLI neurons when it was administered at either 2 days or 2 weeks post nerve injury. At 2 days, injection of the local anesthetic subcutaneously in the dorsum of neck, to control for a systemic action, also reduced expression of FLI in laminae 1 and 2; at 2 weeks, the systemic injection of the local anesthetic reduced expression of FLI throughout the gray matter of the spinal cord. These results demonstrate that peripheral nerve injury, in contrast to tissue injury, induces a prolonged increase in Fos expression in neurons predominantly in those regions of the spinal cord that are associated with the transmission of nociceptive messages. This pattern of fos-like immunoreactivity is probably the result of persistent neuronal activity in the spinal cord. The increased 'activity' in the spinal cord appears to be maintained both by abnormal activity in the injured peripheral nerve as well as by reorganization of circuits within the spinal cord secondary to the nerve injury.

Anesthetics, Local↗
PubMed1993

GABAergic regulation of noradrenergic spinal projection neurons of the A5 cell group in the rat: an electron microscopic analysis.

Recent studies have demonstrated an important contribution of the A5 noradrenergic cell group of the rostral medulla in the regulation of nociceptive messages at the level of the spinal cord. These noradrenergic controls parallel those arising from the serotonin-containing neurons of the nucleus raphe magnus. In the present study, we used postembedding immunogold staining to identify GABA-immunoreactive terminals that synapse upon identified spinally projecting noradrenergic neurons of the A5 cell group in the rat. A5 projection neurons were identified by Fluoro-Gold transport from the spinal cord; sections containing retrogradely labelled cells were then immunoreacted for tyrosine hydroxylase (TH) to identify the catecholamine-containing, presumed noradrenergic, neurons. Double-labelled A5 cells were intracellularly filled with Lucifer Yellow (LY) and then the LY was photo-oxidized to an electron-dense product. Seven intracellularly filled TH-immunoreactive projection neurons were studied with postembedding immunocytochemistry. Each A5 neuron received a significant GABA-immunoreactive terminal input. Out of a pooled total of 151 terminal profiles found in apposition to intracellularly labelled somatic and dendritic profiles, 31 (20.5%) were GABA-immunoreactive. The proportion of GABA-immunoreactive terminals that contacted somatic profiles (12/72; 17%) was similar to the proportion that contacted TH-labelled dendritic profiles (19/79; 24%). There was a discernible synaptic specialization in about 50% of the labelled terminals that contacted the TH projection neuron. Both symmetric and asymmetric synaptic specializations were found. Labelled terminals contained round or pleiomorphic vesicles, but not flat vesicles; many also contained dense-core vesicles. Our results indicate that noradrenergic neurons of the A5 cell group, which contribute to both antinociceptive and cardiovascular controls through their projection to the spinal cord, are regulated by local GABAergic, presumably inhibitory, mechanisms. Whether the initiation of A5 neuron activity results from a lifting of tonic GABAergic inhibitory control, as has been proposed for the neurons of the nucleus raphe magnus, remains to be determined.

Animals↗
PubMed1993

Adrenal medullary modulation of the inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine.

In the present experiments, we studied the effect of i.t. nicotine on synovial bradykinin-induced plasma extravasation (BK-PE), assessed by measurement of extravasation of Evan's blue dye into the rat knee joint. We report that in normal rats, i.t. nicotine dose-dependently inhibited BK-PE; the dose required was 100 times greater than the effective s.c. dose. In adrenal medullectomized rats, i.t. nicotine inhibited BK-PE at doses 10(6) times smaller than in rats with intact adrenal medullae. A similar leftward shift in the i.t. nicotine dose-response curve was seen in normal rats after blocking peripheral nicotinic receptors by hexamethonium or after bilateral denervation of the adrenal medulla. Intra-articular infusion of the knee joint in normal rats with knee joint perfusate collected from donor rats that had received i.t. nicotine decreased BK-PE significantly. Denervation of the sciatic nerves in the donor rat did not affect this action of i.t. nicotine. Perfusate collected from adrenal medullectomized donor rats that had received i.t. nicotine resulted in a greater decrease of BK-PE compared to the decrease produced by perfusate from normal donor rats that received i.t. nicotine. Intra-articular pretreatment of recipient rats with different receptor antagonists [phentolamine (alpha adrenoceptors), ICI-118,551 (beta 2 adrenoceptors), methysergide (serotoninergic S1/2 receptors) or naloxone (opioid receptors)] did not affect the BK-PE response produced by this perfusate. Nicotine, when administered i.t., can inhibit synovial BK-PE, but this effect is expressed only at high doses in the presence of an intact adrenal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1993

Peptides and the primary afferent nociceptor.

An expanding knowledge of neuropeptides and their function has led to a profound change in our view of how the PAN contributes to pain. In addition to their expected direct action on postsynaptic cells in the dorsal horn, neuropeptides can modify transmitter release from nearby terminals of other PANs and/or diffuse to act on dorsal horn neurons at a considerable distance from their site of release (Fig. 2). Contrary to early expectations and despite the evidence that several neuropeptides excite central nociceptive neurons, there is no clear correspondence between neuropeptide content and physiologically defined classes of small-diameter primary afferents. There is, however, a tendency for populations of afferents innervating different organs to differ consistently in their peptide content. In fact, the peptide content of primary afferents is, in part, determined by specific factors in the tissues that they innervate. Furthermore, peptide content can change dramatically in response to certain prolonged stimuli or nerve damage. The lack of correspondence of peptide content and physiological response pattern, the plasticity of peptide content, its tissue specificity, and the possibility for action at a distance from the site of their release from central PAN terminals strongly suggest that PAN peptides have functions that are fundamentally different from those of the short-range actions of amino acid neurotransmitters that are also found in the PAN. Finally, nowhere is the plasticity of function of the PAN more evident than at its peripheral terminals. Long-term changes are produced in these terminals by a host of peptides that derive from a variety of cell types. The complexity of this transduction process is augmented by the activity-induced release of peripherally active neuropeptides from the PAN itself. In addition to the variety of fundamental neurobiological issues that recent studies of PANs have raised, they have also generated a great deal of clinical interest, in view of the role of the PAN in inflammation and its accessibility for study and for therapeutic intervention.

Animals↗
PubMed1992

Ultrastructural evidence for GABA-mediated disinhibitory circuits in the spinal cord of the cat.

The synaptic relationships between gamma-aminobutyric acid (GABA)-immunoreactive and enkephalin-immunoreactive profiles in the cat spinal cord were examined using combined pre-embedding immunoperoxidase and post-embedding immunogold electron microscopic immunocytochemistry. Although colchicine was not used, enkephalin-immunoreactive somata and dendrites were detected in regions associated with nociceptive transmission, including laminae I, II, V and X. In each of these laminae, many GABA-immunoreactive terminals were found presynaptic to enkephalin-immunoreactive cell bodies and dendrites. We propose that disinhibition of opioid-containing neurons may be a common feature of pain-related circuits in the cat spinal cord.

Animals↗
PubMed1992

Morphine or U-50,488 suppresses Fos protein-like immunoreactivity in the spinal cord and nucleus tractus solitarii evoked by a noxious visceral stimulus in the rat.

Immunohistochemical visualization of Fos protein, the nuclear phosphoprotein product of the early-immediate gene c-fos, permits identification of populations of neurons that are activated in response to a variety of stimuli. This study examined the distribution of Fos-like immunoreactive (FLI) neurons in the spinal cord and the nucleus tractus solitarii (NTS) of the caudal medulla evoked by a noxious visceral stimulus in the unanesthetized rat. It also compared the inhibition of pain behavior and Fos expression by a mu-selective opioid agonist, morphine, and a kappa-selective opioid agonist, U-50,488. Intraperitoneal injection of 3.5% acetic acid in the unanesthetized rat evoked the expression of FLI in a discrete population of spinal cord neurons, the distribution of which closely mirrored the spinal terminations of visceral primary afferents. Specifically, FLI neurons were concentrated in laminae I, IIo, V, VII, and X. Large numbers of Fos-immunoreactive neurons were also present in the NTS of the caudal medulla, most likely as a result of spinosolitary tract and vaginal afferent input. The number of labeled neurons in both the spinal cord and the NTS was significantly correlated with the number of abdominal stretches, a pain behavior measure. Both morphine (1-10 mg/kg s.c.) and U-50,488 (3-30 mg/kg s.c.) produced a dose-dependent inhibition of the pain behavior in these animals and a dose-dependent suppression of the number of FLI neurons in both the spinal cord and in the NTS; complete suppression of FLI neurons was, however, not necessary for the production of antinociception. Furthermore, although equianalgesic doses of morphine and U-50,488 reduced the number of labelled neurons in the spinal cord to a comparable extent, morphine reduced the number of immunoreactive neurons in the NTS to a greater extent than did U-50,488. These results suggest that morphine and U-50,488 have comparable effects on the transmission of visceral nociceptive messages by spinal neurons, but differentially affect the autonomic response to noxious visceral stimuli.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Construction of a microdialysis probe with attached microinjection catheter.

We describe a microdialysis probe with attached side catheter for making submicroliter injections at the site of the probe in the awake, freely moving rat. This design allows the local application of drugs which cannot be applied in the perfusion medium either because of their inability to pass through the dialysis membrane or because of their interference with chromatographic detection of compounds of interest.

Animals↗
PubMed1992

Chronically administered nicotine attenuates bradykinin-induced plasma extravasation and aggravates arthritis-induced joint injury in the rat.

We recently showed that acute administration of nicotine in the rat decreases bradykinin-induced plasma extravasation and that adrenal medullary-derived epinephrine, acting at a beta 2-adrenergic receptor, mediates the nicotine effect. Since agents which decrease bradykinin-induced plasma extravasation have been associated with increased joint injury in a rat model of chronic inflammation (experimental arthritis induced by subcutaneous injection of Mycobacterium butyricum) we examined the effect of chronic nicotine on both plasma extravasation and the severity of joint injury. In normal rats, bradykinin-induced plasma extravasation was decreased after nicotine administered both by repeated injection (10(-2) mg/kg, s.c., once per h for 4 h) and by continuous long-term infusion (subcutaneous mini-osmotic pump; 1.5 x 10(-3) mg/kg per h for 30 days). Nicotine-induced inhibition of bradykinin-induced plasma extravasation did not show tachyphylaxis. In rats with arthritis, chronic administration of nicotine also produced a decrease in bradykinin-induced plasma extravasation. This effect of chronic nicotine in the arthritic rats was antagonized by co-administration of hexamethonium (a nicotinic receptor antagonist), by surgical removal of the adrenal medulla, or by co-administration of ICI-118,551 (a beta 2-adrenoceptor antagonist). Chronic administration of nicotine decreased the latency to the onset of arthritis and, in a dose-dependent manner, led to an increase in the radiographic joint injury score.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1992

Sensory neuropeptide interactions in the production of plasma extravasation in the rat.

We used an experimental model of neurogenic inflammation to study the contribution of the primary afferent peptides substance P, calcitonin gene-related peptide, galanin and somatostatin to plasma extravasation in rat synovium. Perfusion of the C-fiber excitotoxin, capsaicin (1.6 mM), through the knee joint of the pentobarbital anesthetized rat, increased plasma extravasation transiently (< 30 min). Perfusion of substance P (1 microM) or calcitonin gene-related peptide (100 nM), two primary afferent neuropeptides that are released by acute capsaicin administration, had no significant effect on plasma extravasation. Co-perfusion of these two neuropeptides, however, evoked an increase in plasma extravasation that was greater than that produced by capsaicin remaining above 250% of the baseline level by the end of the perfusion period (55 min). Capsaicin co-perfused with either galanin (100 nM) or somatostatin (1 microM) failed to increase plasma extravasation. Neither galanin nor somatostatin significantly affected increase in plasma extravasation induced by co-perfusion of substance P plus calcitonin gene-related peptide. Therefore, we suggest that galanin and somatostatin inhibit, presynaptically, the release of substance P and calcitonin gene-related peptide from primary afferent terminals. The interactions among these four neuropeptides provide a novel mechanism for the regulation of primary afferent neurogenic inflammation.

Animals↗
PubMed1992

Simultaneous measurement of extracellular morphine and serotonin in brain tissue and CSF by microdialysis in awake rats.

In this report, we describe an HPLC with electrochemical detection assay for the simultaneous measurement of levels of morphine, serotonin, 5-hydroxyindole-3-acetic acid, and homovanillic acid in dialysates of various brain areas and CSF in the awake rat. Morphine could be detected in the dialysates after a single intraperitoneal injection, with doses as low as 1.0 mg/kg. The time course of extracellular morphine content in the lateral hypothalamus, striatum, cerebellum, periaqueductal gray, and dorsal horn of the spinal cord and in CSF, from the ventricles and cisterna magna, was similar. We detected morphine in the first 15-min sample, and levels peaked 45-60 min after injection. Maximal dialysate levels, however, varied with the type of dialysis probe used and the area sampled. The most efficient in vivo recovery was in CSF dialysates from the cisterna magna, presumably because of minimal tissue interference with the dialysis probe. For this reason, the cisterna is an ideal region for sampling CSF. Morphine had no significant effect on the extracellular concentrations of serotonin in any of the areas studied and did not modify or only slightly increased levels of tissue metabolites; however, morphine markedly increased the CSF levels of 5-hydroxyindole-3-acetic acid and homovanillic acid. Because microdialysis in freely moving animals permits assessment of the behavioral effects of morphine while continuously monitoring the drug levels in discrete brain regions, this approach will greatly facilitate future studies of the neurochemical basis of morphine's effects in the brain.

Animals↗
PubMed1992

Medullary CO2 chemoreceptor neuron identification by c-fos immunocytochemistry.

In a search for CO2 chemoreceptor neurons in the brain stem, we used immunocytochemistry to monitor the expression of neuronal c-fos, a marker of increased activity, after 1 h of exposure to CO2 in five groups of Sprague-Dawley rats (294 +/- 20 g): five air breathing controls, three breathing 10% CO2, three breathing 13% CO2, three breathing 15% CO2, and three breathing 15% CO2 and treated with morphine (10 mg/kg sc). After exposure the rats were anesthetized with pentobarbital sodium and perfused intracardially with 4% paraformaldehyde. The brain stem was removed and cryoprotected, and then 50-microns frozen sections were cut and immunostained for the fos protein. Brain stem fos-immunoreactive neurons were plotted and counted in the superficial 0.5 mm of the ventral medullary surface. Thirteen to 15% CO2 evoked fos-like immunoreactivity (FLI) in 321 +/- 146 neurons/rat. Significant CO2-induced labeling was confined within the superficial 150 microns: 67% of identified cells were less than 50 microns below the surface, greater than 90% between 1.0 and 3.0 mm from the midline, and approximately 60% in the rostral half of the medulla. Thirteen to 15% CO2 also evoked FLI in the area of the nucleus tractus solitarius but not in other medullary regions. Morphine (10 mg/kg sc) did not suppress high CO2-evoked FLI in either the ventral medullary surface or the nucleus tractus solitarius, although it eliminated excitement and hyperventilation. We suggest that respiratory CO2 chemoreceptor neurons can be identified in rats by their expression of c-fos after 1 h of hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗