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Biomedical subjects

A I Basbaum

Publications and source records attributed to A I Basbaum.

At least 109 records · Page 6Linked to original sources
PubMed1992

The origin of brainstem noradrenergic and serotonergic projections to the spinal cord dorsal horn in the rat.

Although it has been proposed that the locus coeruleus is the predominant, if not exclusive, brainstem origin of the noradrenergic innervation of the spinal dorsal horn, pharmacological studies argue otherwise. In this study we made localized injections of the retrograde tracer wheatgerm agglutinin conjugated to apo-horseradish peroxidase gold (WGA:apoHRP-Au), in conjunction with immunocytochemical labeling for tyrosine hydroxylase (TH) or serotonin (5-HT), to identify the brainstem source of the noradrenaline (NA) and 5-HT innervation of the dorsal horn of the rat. Our studies were concentrated in the C5 spinal segment. The pattern of labeling was only studied in animals in which the tracer injection was restricted to the dorsal horn. In these rats, TH-immunoreactive neurons in widespread regions of the brainstem, including the locus coeruleus, subcoeruleus, A5, and A7 cell groups, were found to project to the dorsal horn. In terms of absolute numbers of double-labeled cells, no one noradrenergic cell group predominated. As expected, dorsal-horn-projecting 5-HT-immunoreactive neurons were found within the 5-HT populations of the rostroventromedial medulla and caudal pons, including the nucleus raphe magnus, nucleus paragigantocellularis (PGi), and ventral portions of the nucleus gigantocellularis (Gi). The majority of retrogradely labeled 5-HT-immunoreactive cells were, however, located off the midline, in the ipsilateral PGi and ventral Gi. Finally, a large number of retrogradely labeled, non-5-HT cells were found intermingled among the 5-HT cells of this region. Our results provide evidence that the noradrenergic regulation of nociceptive transmission at the spinal cord level arises from direct spinal projections of several brainstem noradrenergic cell groups.

Animals↗
PubMed1992

Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinin-induced plasma extravasation in the knee joint of the rat.

Previous results from this laboratory demonstrated that plasma extravasation produced by intra-articular infusion of bradykinin in the rat is mediated by an action on the sympathetic terminals in the knee joint and that adrenal medullary epinephrine regulates the plasma extravasation provoked by bradykinin. Because the release of epinephrine is under cholinergic control, we have now evaluated the effect of nicotinic and muscarinic cholinergic agonists on bradykinin-induced plasma extravasation in the knee joint of the rat. We report that s.c. administration of nicotine and carbachol attenuated plasma extravasation induced by bradykinin; this attenuation was significantly antagonized by systemic injection of hexamethonium and atropine, respectively. The nicotine and carbachol effects were also significantly attenuated after removal of the adrenal medulla. These results indicate that both nicotine and carbachol can inhibit bradykinin-induced plasma extravasation and that this inhibition is mediated, at least in part, through activation of nicotinic and muscarinic receptors in the adrenal medulla. Finally, local perfusion of the knee joint with hexamethonium did not affect the inhibition of bradykinin-induced plasma extravasation produced by systemic nicotine. Intra-articular perfusion of atropine potentiated the inhibition of bradykinin-induced plasma extravasation by systemic carbachol, indicating that muscarinic receptors in the synovium also contribute to plasma extravasation. The inhibitory action of nicotine on plasma extravasation may contribute, in part, to the reported increased severity of arthritis in individuals who smoke.

Adrenal Medulla↗
PubMed1991

Sympathetic neuron factors involved in bradykinin-induced plasma extravasation in the rat.

Previous studies have demonstrated that bradykinin (BK) produces a sympathetically dependent plasma extravasation into the rat knee joint which is, in part, dependent upon the production of a prostaglandin. In the present study, co-administration of the specific prostaglandin, PGE2, markedly enhanced the BK-induced plasma extravasation. In this study we also report that after chemically induced sympathectomy, by chronic pretreatment with 6-hydroxydopamine (6-OHDA), both the plasma extravasation produced by BK and the enhancing effect of PGE2 are markedly attenuated. Plasma extravasation induced by PGE2 alone was small and was not significantly attenuated by sympathectomy. We conclude that BK-induced extravasation involves production of at least two sympathetic postganglionic neuron (SPGN) terminal-dependent factors, one of which is a cyclo-oxygenase product of arachidonic acid metabolism, probably PGE2, (Coderre et al., J. Neurophysiol., 62 (1989) 45-58) and another that is unidentified.

Animals↗
PubMed1991

Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat.

We assessed the contribution of ATP and adenosine (i) to a major sign of acute inflammation, plasma extravasation (PE), in the rat knee joint and (ii) to the severity of joint injury in adjuvant-induced experimental arthritis, a chronic inflammatory disease. PE induced by local infusion of bradykinin, which we have previously shown to depend on the sympathetic postganglionic neuron terminal, was markedly enhanced by coinfusion of either ATP or the adenosine A2-receptor agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine. Bradykinin-induced PE was inhibited by coinfusion of the ATP receptor antagonist adenosine 5'-[alpha,beta-methylene]triphosphate, the A2-receptor antagonist 3-(5H-thiozolo[2,3b]quinazolin-3-yl)phenol monohydrochloride, or the adenosine A1-receptor agonist N6-cyclopentyladenosine. The joint injury associated with experimental arthritis, which is reduced in severity in sympathectomized rats, was also markedly attenuated by daily administration of either ATP (40% reduction) or adenosine (55% reduction). These results demonstrate that the purines ATP and adenosine (acting at the A2 receptor), cotransmitters in the sympathetic postganglionic neuron terminal, enhance bradykinin-induced sympathetic postganglionic neuron terminal-dependent PE but inhibit the joint injury of arthritis. These opposing purinergic effects on PE and joint injury suggest that enhanced PE protects against joint injury.

Adenosine↗
PubMed1991

High-dose epinephrine acts at alpha 2-adrenoceptors to suppress experimental arthritis.

This study assessed the receptor site at which high systemic doses of epinephrine act to reduce the severity of adjuvant-induced arthritis in the rat. To this end we examined the effect of selective adrenergic antagonists on the reduction of arthritis by epinephrine, and also assessed whether high doses of selective adrenergic agonists mimicked the effect of epinephrine. The decrease in arthritis induced by epinephrine (0.5 mg/kg in chronic implant injected every 3 days) was significantly antagonized by the selective alpha 2-adrenergic antagonist, yohimbine, but not by selective alpha 1 (prazosin), beta 1 (metoprolol) or beta 2 (butoxamine) antagonists. In addition, chronic infusion of the alpha 2-adrenergic agonist clonidine, but not selective alpha 1 (phenylephrine), beta 1/beta 2 (isoproterenol) or beta 2 (salbutamol) agonists, resulted in decreased arthritis severity. These data suggest that the suppressive effect of high-dose epinephrine on joint injury in experimental arthritis is mediated by action at the alpha 2-adrenergic receptor.

Adrenergic alpha-Agonists↗
PubMed1991

GABAergic circuitry in the rostral ventral medulla of the rat and its relationship to descending antinociceptive controls.

This study used postembedding immunocytochemistry to examine the organization of GABA-immunoreactive synapse in the rostral ventral medulla (RVM) of the rat. To determine whether the outflow neurons of the RVM are under GABAergic control, we examined the distribution of GABA-immunoreactive synapses upon bulbospinal projection neurons that were labelled by retrograde transport of wheatgerm agglutinin-HRP from the cervical spinal cord. To study the possible convergence of GABAergic and periaqueductal gray (PAG) synaptic inputs to RVM neurons, we also made lesions in the PAG and examined the relationship between degenerating PAG axons and GABA-immunoreactive terminals. Approximately 45% of all synapses in the RVM, which includes the midline nucleus raphe magnus and the nucleus reticularis paragigantocellularis lateralis, were GABA-immunoreactive. The vast majority of GABA-immunoreactive terminals contained round, clear, and pleomorphic vesicles and made symmetrical axodendritic synapses; axoaxonic synapses were not found. Almost 50% of the retrogradely labeled dendrites in the NRM were postsynaptic to GABA-immunoreactive terminals. Several examples of convergence of degenerating PAG terminals and GABAergic terminals onto the same unlabelled dendrite were also found. These data indicate that the projection neurons of the RVM are under profound GABAergic inhibitory control. The results are discussed with regard to the hypothesis that the analgesic action of narcotics and electrical stimulation of the midbrain PAG involves the regulation of tonic GABAergic inhibitory controls that are exerted upon spinally-projecting neurons of the nucleus raphe magnus.

Animals↗
PubMed1991

The spectrum of fiber loss in a model of neuropathic pain in the rat: an electron microscopic study.

Recently, Bennett and Xie reported that when the sciatic nerve of the rat is ligated loosely, the rat develops a pain syndrome with many features similar to those observed in neuropathic pain states in man. Anatomical and physiological studies to date indicate that the major pathology is a loss of large diameter myelinated fibers distal to the ligatures, with more subtle changes in small myelinated fibers. With a view to evaluating possible changes in the unmyelinated fibers, we have performed an electron microscopic analysis of the sciatic nerve 2 weeks after four ligatures were applied, at which time the animals displayed profound hyperalgesia and mechanical and thermal allodynia. Cross-sectional photomontages of regions proximal and distal to the ligatures were studied. Consistent with light microscopic and electrophysiological studies, we found a near complete loss of large myelinated fibers distal to the ligatures. Phagocytosis of large fibers was common. There was also considerable variation in the damage to small myelinated fibers. In some fascicles many small (less than 3 microns) myelinated axons remained; in other fascicles none could be detected. Importantly, we also found significant changes in the unmyelinated fiber spectrum. Counts of unmyelinated axons revealed a 34% and 71% decrease in the distal compared to the proximal nerve, in the two rats studied. The large clusters of unmyelinated axons that characterize normal nerve (and the nerve proximal to the ligatures) were rarely found distally. Rather, many of the unmyelinated axons coursed singly or in very loose bundles. Many of the surviving axons were shrunken and distorted, although still in contact with Schwann cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The antinociceptive action of supraspinal opioids results from an increase in descending inhibitory control: correlation of nociceptive behavior and c-fos expression.

In an earlier report, we demonstrated that subcutaneous injection of formalin in the rat hindpaw evokes a characteristic pattern of expression of the fos protein product of the c-fos protooncogene in spinal cord neurons, and that systemic morphine reversed the fos-like immunoreactivity in a dose-dependent, naloxone-reversible manner. The present study compared the effects of intracerebroventricular administration of the mu-selective opioid ligand [D-Ala2, NMe-Phe4, Gly-ol5] enkephalin, on the pain behavior and spinal cord fos-like immunoreactivity produced by subcutaneous formalin. Formalin injection produced a biphasic pain behavioral response which lasted about 1 h. There was a significant correlation between the formalin pain score and overall fos-like immunoreactivity in the lumbar enlargement. The greatest numbers of labeled cells and most intense fos-like immunoreactivity were found in laminae I, IIo and V of the L4-5 segments, ipsilateral to the formalin-injected paw. Considerable staining was also found in the ipsilateral ventral horn laminae VII and VIII. [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin produced a dose-related, naloxone-reversible inhibition of both the formalin-evoked pain behavior and fos expression in the cord. The behavioral response to formalin, however, could be completely blocked without eliminating the expression of fos in spinal neurons. Moreover, subpopulations of neurons were differentially regulated. Thus, 100% inhibition of pain behavior was produced at a dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which reduced fos-like immunoreactivity in the superficial laminae by only 64% and in the neck and ventral cord by 85%. Furthermore, the dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which produced approximately 50% inhibition of fos-like immunoreactivity in the neck and ventral regions of the spinal cord was without effect in the superficial dorsal horn. Since the potencies for inhibition of pain behavior and fos-like immunoreactivity in the neck and ventral horn were comparable, these data suggest that the activity of neurons in these regions is directly related to the pain behavior produced by nociceptive inputs. Finally, we found that bilateral, midthoracic lesions of the dorsal part of the lateral funiculus blocked both the antinociception and fos suppression produced by intracerebroventricular [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin. These results are consistent with the hypothesis that the analgesic action of supraspinally administered opiates results from an increase in descending inhibitory controls that regulate the firing of subpopulations of spinal cord nociresponsive neurons.

Amino Acid Sequence↗
PubMed1991

Collateralization of periaqueductal gray neurons to forebrain or diencephalon and to the medullary nucleus raphe magnus in the rat.

Antinociceptive effects elicited from the midbrain may involve both ascending and descending projections from the periaqueductal gray and dorsal raphe nucleus. To investigate the relationship between these different efferent pathways in the rat, we performed a double-labeling study using two retrograde tracers, colloidal gold-coupled wheatgerm agglutinin-apo horseradish peroxidase and a fluorescent dye. One tracer was microinjected in the medullary nucleus raphe magnus; the second was injected into one of several regions rostral to the periaqueductal gray that have been implicated in nociceptive and antinociceptive processes. The results can be grouped into two categories. First, injections into the ventrobasal thalamus, lateral hypothalamus, amygdala, and cerebral cortex labeled neurons in the dorsal raphe nucleus but not in the periaqueductal gray. Up to 90% of these projection neurons were serotonin immunoreactive, and up to 17% were also retrogradely labeled from the nucleus raphe magnus. Second, only injections into the ventrobasal hypothalamus (which included the beta-endorphin-containing arcuate neurons) or into the medial thalamus labeled neurons in the periaqueductal gray itself. Injections into the medial thalamus, but not into the ventrobasal hypothalamus, also labeled neurons in the dorsal raphe nucleus. Up to 20% of the neurons retrogradely labeled from these regions were also retrogradely labeled from nucleus raphe magnus. The presence of large populations of rostrally projecting periaqueductal gray neurons that collateralize to the nucleus raphe magnus implies that activity in ascending projections necessarily accompanies any activation of the periaqueductal gray-nucleus raphe magnus pathway. Possibly, projections from the medial thalamus and medial hypothalamus mediate antinociceptive effects that complement descending inhibition. Finally, possible antidromic activation of these pathways must be considered when interpreting the results of electrical brain stimulation studies.

Animals↗
PubMed1991

Increasing sympathetic nerve terminal-dependent plasma extravasation correlates with decreased arthritic joint injury in rats.

This study compared the pharmacology of adrenergic agents that influence plasma extravasation in normal animals with those agents that influence tissue injury in an inflammatory disease model. Specifically we studied the effects of beta 2- and alpha 2-adrenergic receptor agonists and antagonists on bradykinin-induced plasma extravasation in normal Sprague-Dawley rats and on joint injury in rats with experimental arthritis. Plasma extravasation induced by infusion of bradykinin in the rat knee joint was attenuated by the beta 2-agonist salbutamol or by the alpha 2-antagonist yohimbine, and was enhanced by the beta 2-antagonist, ICI-118,551, or by the alpha 2-agonist, clonidine. In rats that had undergone chemical symphathectomy, bradykinin-induced plasma extravasation was markedly reduced, and there was no enhancement of bradykinin-induced plasma extravasation by either ICI-118,551 or clonidine. Although ICI-118,551 and clonidine enhanced bradykinin-induced plasma extravasation, these drugs significantly reduced joint injury in rats with adjuvant-induced arthritis. Neither salbutamol nor yohimbine, however, significantly increased joint injury in the arthritic rats, presumably because arthritis severity is already high in these animals. Consistent with this hypothesis, both salbutamol and yohimbine did significantly increase the joint injury associated with experimental arthritis in Wistar-Kyoto rats, a strain which develops a mild adjuvant arthritis. The fact that increased plasma extravasation is associated with decreased arthritis severity suggests that plasma extravasation, a major sign of acute inflammation, contributes to tissue reparative processes.

Animals↗
PubMed1991

Neutrophils contribute to sympathetic nerve terminal-dependent plasma extravasation in the knee joint of the rat.

Infusion of bradykinin or 6-hydroxydopamine into the knee joint of the rat activates sympathetic postganglionic nerve terminals and increases plasma extravasation, a major sign of acute inflammation. Since bradykinin attracts and activates neutrophils in vivo and since neutrophils can release factors leading to plasma extravasation, we evaluated the contribution of the neutrophil to bradykinin-induced plasma extravasation. We report that perfusion of bradykinin into the rat knee joint produces a prolonged increase in plasma extravasation which is markedly reduced not only by sympathectomy (chronic pretreatment with systemic 6-hydroxydopamine) but also by depletion of circulating polymorphonuclear leukocytes (intravenous infusion of hydroxyurea combined with intraperitoneal glycogen). Depletion of polymorphonuclear leukocytes also reduced the plasma extravasation induced by intra-articular infusion of 6-hydroxydopamine, which acutely activates sympathetic postganglionic terminals. We next tested whether attraction of neutrophils into the joint, in the absence of bradykinin, was sufficient to enhance plasma extravasation. Although the classical neutrophil attractant glycogen attracted neutrophils into the knee joint, it did not increase plasma extravasation. Co-infusion of bradykinin and glycogen into the knee joint, however, provoked plasma extravasation that was significantly greater than that produced by bradykinin alone. We hypothesize, therefore, that bradykinin not only attracts neutrophils but also activates them, by an as yet undefined mechanism that requires the sympathetic terminal. The activated neutrophils release factors that lead to plasma extravasation. The next series of studies evaluated the role of the sympathetic nervous system in neutrophil attraction in vivo by bradykinin and glycogen. Since quantification of neutrophil attraction was not possible in the knee joint, we performed these studies in the peritoneal cavity, a site where neutrophils are readily attracted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The contribution of the nervous system to inflammation and inflammatory disease.

Recent studies have identified a major contribution of the nervous system to inflammation and to inflammatory disease. In particular, substances released from the peripheral terminals of small diameter primary afferent fibers and from sympathetic postganglionic nerve (SPGN) terminals have been implicated in several of the major components of acute inflammation (e.g., vasodilatation and plasma extravasation) as well as in the regulation of tissue injury in an inflammatory disease model, experimental arthritis in the rat. Although the release of peptides from primary afferent terminals has received the most attention, our studies have established an important contribution of mast cells and the SPGN terminals to acute inflammation. We describe studies which indicate that plasma extravasation provoked by activation of small diameter primary afferents in the knee joint of the rat involves a cascade of events in which the mast cell and then the sympathetic terminal are sequentially activated. Our studies indicate that release of prostaglandins, but neither norepinephrine nor neuropeptide Y, from the SPGN terminal contributes to increased plasma extravasation. Although activation of the SPGN terminal (via the mast cell) or more directly, via injection of bradykinin, increased plasma extravasation, surgical or pharmacological sympathectomy decreased the severity of experimental arthritis. In related studies we demonstrated that adrenal medullary-derived epinephrine can exacerbate arthritis through a beta-receptor-mediated regulation of the release of an as yet unidentified substance(s) from the SPGN terminal. Our results raise important questions as to whether acute inflammation contributes to tissue repair or to further injury in the setting of disease.

Animals↗
PubMed1990

Contribution of brainstem GABAergic circuitry to descending antinociceptive controls: I. GABA-immunoreactive projection neurons in the periaqueductal gray and nucleus raphe magnus.

The fact that GABA receptor agonists and antagonists influence nociceptive thresholds when microinjected into the rostroventral medulla or in the spinal cord may reflect the involvement of GABAergic neuronal elements in endogenous antinociceptive pathways. In the present study we used immunocytochemistry and retrograde tract tracing to investigate the contribution of GABAergic projection neurons to the antinociceptive network linking the midbrain periaqueductal gray matter (PAG), the nucleus raphe magnus (NRM), and the spinal cord dorsal horn. The tracer, WGAapoHRP-Au was injected into either the NRM or the spinal cord and the distribution of labeled neurons in sections of the PAG and medulla, respectively, was studied. The same sections were immunostained to demonstrate GABA-immunoreactive neurons. Although GABA-immunoreactive neurons were abundant in the PAG, only 1.5% were retrogradely labeled from the NRM. Similarly, very few GABA-immunoreactive neurons within the cytoarchitectural boundaries of the NRM were retrogradely labeled from the spinal cord. A much higher proportion of GABA-immunoreactive neurons in the region lateral to the NRM, however, were retrogradely labeled from the spinal cord. Eighteen percent of GABA-immunoreactive neurons were retrogradely labeled in the nucleus reticularis paragigantocellularis; conversely, 15% of the retrogradely labeled neurons in this region were GABA-immunoreactive. These results indicate that GABAergic projections constitute a very minor component of the PAG-NRM-spinal cord pathway; however, there is a significant contribution of GABAergic neurons to the spinal projections that originate lateral to the NRM. The majority of GABAergic neurons in the PAG and NRM are presumed to be inhibitory interneurons that directly or indirectly regulate activity in efferent pathways from these regions.

Animals↗
PubMed1990

Contribution of brainstem GABAergic circuitry to descending antinociceptive controls: II. Electron microscopic immunocytochemical evidence of GABAergic control over the projection from the periaqueductal gray to the nucleus raphe magnus in the rat.

Pharmacological, physiological, and behavioral studies suggest that inhibitory GABAergic neurons influence the projection from the midbrain periaqueductal gray matter to the medullary nucleus raphe magnus. The present study used electron microscopic immunocytochemical techniques to examine the morphology and synaptic relationships of GABA-immunoreactive terminals in the ventrolateral periaqueductal gray. These putative GABAergic terminals comprise almost 40% of all axon terminals in the periaqueductal gray. GABA-immunoreactive terminals contain small, clear, pleomorphic or round, vesicles, and 46% also contain some dense-cored vesicles. In some experiments we also used a colloidal gold-conjugated retrograde tracer to label periaqueductal gray neurons that project to the nucleus raphe magnus. About half of the synaptic inputs onto the cell bodies and proximal dendrites of retrogradely labeled neurons are GABA-immunoreactive; these putative GABAergic synapses, which directly control activity in neurons projecting from the periaqueductal gray to the nucleus raphe magnus, might mediate the antinociception-related effects of exogenous GABAA receptor ligands.

Animals↗
PubMed1990

Denervation-induced inflammation in the rat.

We report that section of the sciatic and saphenous nerves, in the hindlimb of the rat, evokes an inflammatory response in the denervated tissue that can be distinguished from the previously described peptide-mediated neurogenic inflammation. This novel form of neurogenic inflammation has a very delayed onset (9.75 +/- 2.1 h, mean +/- S.E.M., n = 8), persists for more than 30 h, and is characterized by a marked neutrophilic cellular infiltrate. These features cannot be mimicked by electrical stimulation of the peripheral nerve and are not prevented by either prior application of local anesthetics to the nerve lesion site or by neonatal treatment with capsaicin.

Animals↗
PubMed1990

Characterization of monoamine release in the lateral hypothalamus of awake, freely moving rats using in vivo microdialysis.

Extracellular levels of serotonin (5-HT), dopamine (DA) and their major metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were measured in the lateral hypothalamus of awake, freely moving rats using microdialysis combined with HPLC and electrochemical detection. To characterize the factors which control 5-HT release, the effects of various drugs were assessed. TTX had a reversible inhibitory effect on the basal levels of 5-HT, 5-HIAA, DOPAC and HVA. Infusion of K+ concomitantly increased 5-HT and DA and decreased 5-HIAA and HVA. Imipramine increased extracellular levels of 5-HT and DA and decreased 5-HIAA levels; this effect was TTX-sensitive. Systemic pargyline increased extracellular 5-HT and markedly decreased the metabolic levels. Pargyline pretreatment in the presence of imipramine, infused through the dialysis probe, slowly increased 5-HT levels above that produced by the reuptake blocker alone. Infusion with AMPH produced a dramatic, TTX-insensitive, increase in 5-HT and DA and a decrease in the metabolic levels. These results provide evidence that (1) basal release of 5-HT in the lateral hypothalamus results from neuronal activity, (2) the metabolites in the extracellular fluid derive primarily from intracellular monoamine oxidase (MAO) activity, (3) 5-HT is mainly removed from the extracellular space by a reuptake mechanism, with minimal contribution of an extracellular MAO, and (4) the AMPH-evoked release of 5-HT and DA is a Na+ channel-independent process.

Amphetamine↗
PubMed1990

Organization of tyrosine hydroxylase- and serotonin-immunoreactive brainstem neurons with axon collaterals to the periaqueductal gray and the spinal cord in the rat.

Retrograde tracing and immunocytochemistry were used to examine the axon collateralization of brainstem serotonin (5-HT) and norepinephrine (NE) cells to the periaqueductal gray (PAG) and spinal cord. Tyrosine hydroxylase (TH)-immunofluorescent neurons which collateralize to the PAG and the cervical spinal cord were found in all brainstem catecholamine cell groups previously shown to contain neurons which project to the spinal cord, including the A5 and A7 cell groups, locus coeruleus, subcoeruleus and the C1 cell group. Many TH-immunofluorescent cells which project to the PAG but not to the spinal cord were also found. The region of the nucleus raphe magnus (NRM) also contained many neurons retrogradely labeled from the PAG. These overlapped with the distribution of spinally projecting 5-HT-immunofluorescent cells in the NRM, however, less than 1% of the PAG projecting cells in this region were 5-HT-immunofluorescent. In contrast, many 5-HT-immunofluorescent cells in the more rostral nucleus raphe pontis and nucleus raphe dorsalis were retrogradely labeled from the PAG but not from the spinal cord. Finally, a population of neurons in the NRM and adjacent reticular formation and in the region of several pontomedullary catecholamine cell groups collateralized to the PAG and spinal cord, but were neither 5-HT nor TH-immunofluorescent. Taken together, these findings raise the possibility that the noradrenergic contribution to the spinal antinociceptive effects produced by PAG electrical stimulation results, in part, from antidromic activation of brainstem noradrenergic neurons that have axon collaterals projecting to the PAG and spinal cord. In contrast, the 5-HT contribution to the spinal antinociceptive effects produced by PAG electrical stimulation is more likely to derive, as previously proposed, from orthodromic activation of raphe-spinal serotonergic axons.

Animals↗