[Relation between GABAergic and dopaminergic neurons in the basal ganglia].
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Animals↗
Biomedical subjects
J M Besson
Publications and source records attributed to J M Besson.
Opioid receptor types and antinociceptive activity in chronic inflammation: both kappa- and mu-opiate agonistic effects are enhanced in arthritic rats.
The antinociceptive effects obtained in arthritic rats with morphine, the opioid mu-agonist DAGO [D-Ala2,MePhe4,Gly-ol5]enkephalin, the delta-selective agonist DTLET [D-Thr2, Leu5]enkephalyl-Thr, and the kappa-agonist U-50,488H were compared to their corresponding effects in normal animals and morphine-pretreated arthritic rats, respectively, using a paw pressure test. The effects of the mu- and kappa-agonists were increased in arthritic rats. While morphine-treated rats were cross-tolerant to the mu- and kappa-agonists, no tolerance to the delta-selective agonist was found. The possibility that the potent action of morphine in this model for chronic inflammatory pain is mediated partly through kappa-mechanisms is discussed.
Analgesics↗
Behavioral evidence for a crossed ascending pathway for pain transmission in the anterolateral quadrant of the rat spinal cord.
Thresholds of two behavioral responses to noxious pressure of the hindpaws (withdrawal, vocalization) were analyzed before and 3 weeks after a lesion of various quadrants of the spinal cord at the cervical level. The threshold of the spinal reflex could not be modified. Threshold of vocalization elicited by the pressure of one hindpaw was significantly increased when, and only when, the opposite ventrolateral quadrant was cut. These results emphasize the role of the lateral spinothalamic tract in the transmission of noxious messages.
Afferent Pathways↗
Slow and fast axonal transport of acetylcholinesterase molecular forms in polyarthritic rats.
Acetylcholinesterase (AChE) activity and its distribution among different molecular forms were studied in the sciatic nerve of normal and polyarthritic rats. Axonal transport of each form was investigated on the basis of its accumulation on both sides of a transection. Although an increase in total AChE activity could be detected in the sciatic nerves of polyarthritic animals, both anterograde and retrograde axonal transport of all the molecular forms investigated were similar in normal and polyarthritic rats. This suggests that neither slow nor fast axonal transport is impaired in polyarthritic rats. Hence, the neurophysiological modifications observed at the spinal, thalamic and cortical levels of the CNS are presumably not a consequence of peripheral axonal disability.
Acetylcholinesterase↗
Increased norepinephrine and uric acid levels in the spinal cord of arthritic rats.
The purpose of the present study was to investigate whether the level of norepinephrine and its rate of disappearance after decarboxylase inhibition were modified in the spinal cord of a chronic pain model: the arthritic rat. Chromatographic studies allowing the simultaneous determination of norepinephrine and uric acid by means of HPLC with electrochemical detection are described. The norepinephrine and uric acid levels in the spinal cord were higher in arthritic rats than in normal rats. In addition the rate of disappearance of the amine was increased in the dorsal part of the cord in arthritic rats. These results agree with previous reports suggesting an activating effect of nociceptive stimuli on descending noradrenergic systems. They also indicate that studies on purine metabolism in the CNS in inflammatory and/or pain processes will be of interest.
Animals↗
Analgesia produced by low doses of the opiate antagonist naloxone in arthritic rats is reduced in morphine-tolerant animals.
In a model of experimental chronic pain (adjuvant-induced arthritic rats), low doses of the opiate antagonist naloxone produced a profound analgesia. Maximum analgesia was seen with 3 micrograms/kg (i.v.). In contrast, hyperalgesia was obtained with much higher doses (1-3 mg/kg, i.v.). The hyperalgesic effects were not affected in arthritic animals rendered tolerant to morphine, but the paradoxical analgesic effects were significantly reduced. This decrease suggests that naloxone analgesia involves interaction with opiate receptors and that the operation of endorphinergic systems differs in normal animals and animals which experience persistent pain.
Animals↗
The overlap of spinothalamic and dorsal column nuclei projections in the ventrobasal complex of the rat thalamus: a double anterograde labeling study using light microscopy analysis.
Projections from the spinal cord and the dorsal column nuclei (DCN) to the ventrobasal complex of the thalamus (VB) were studied in the rat by using double anterograde labeling strategy. This strategy was based on the injection of 3H-leucine into the DCN and of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the spinal cord and their subsequent transport. Adjacent 30-micron-thick sections were then processed differentially for autoradiography or for HRP by using tetramethyl benzidine (TMB) as a chromogen. Similar areas of the ventrobasal complex were labeled, in adjacent sections, after a large injection of 3H-leucine into the DCN and when wheat germ agglutinin-HRP had been injected in any part of the spinal cord. If, however, a small injection of the radioactive tracer was centered in the gracile nucleus and compared with an injection of WGA-HRP placed in the lumbar enlargement of the cord, the rostral and dorsal portions of the lateral VB were labeled from both sources. On the other hand, if tritiated leucine was injected into the cuneate nucleus, and WGA-HRP placed in the cervical enlargement, then the caudal and ventral portions of the lateral VB demonstrated overlap of both labels. The present results show that, in the rat, areas of termination of both the spinothalamic tract and the lemniscal pathway originating from the DCN overlap in the lateral VB. This overlap is somatotopically organized, thus indicating that the same area of the VB receives somatic inputs from one particular part of the body through both pathways. These results are discussed in comparison to those of comparable studies performed in the cat and in the monkey and with reference to the electrophysiological data that have demonstrated that, in the rat VB, neurons responding to noxious stimulation are intermingled with neurons exclusively responding to non-noxious stimulation.
Afferent Pathways↗
[Peripheral and spinal mechanisms of nociception].
Due to the combination of multidisciplinary studies, the last fifteen years have seen a major step forward in our knowledge of nociception. At the peripheral level the role of A delta and C polymodal cutaneous nociceptors is relatively well demonstrated in animal as well as in man. The activation of these nociceptors probably results from both direct effects of the stimulus and indirect effects, mediated by the release of various chemicals. The specific roles of articular, muscular and visceral fine afferent fibers in nociception, is less well understood. Cutaneous A delta and/or C fibers terminate mainly in the superficial zones (laminae I and II outer) of the dorsal horn. The nature of the transmitter (s) released by nociceptive afferents is still unknown. Substance P has long been a candidate but the multiplicity of peptides revealed by immunohistochemical techniques and their coexistence on occasions in the same dorsal root ganglion cells question a unequivocal role of substance P. At the level of the dorsal horn of the spinal cord, nociceptive specific and nociceptive non-specific units have been described in laminae I, II, IV to VI. It is generally held that nociceptive specific neurons are mainly found in the superficial laminae which also contains nociceptive non specific cells. Convergence of cutaneous, muscular and visceral inputs on these neurons is indicative of a role of both cell types in referred pain where consideration must also be given to the possibility of dichotomizing afferent fibers serving cutaneous and visceral territories. The involvement of contralateral ascending pathways (spinothalamic and spinoreticular tracts) in the transmission of nociceptive messages toward supraspinal structures is well established while the role of ipsilateral ascending systems (spino-cervical and dorsal columns post-synaptic fibers) is still questioned. Both segmental and descending modulating controls are exerted at the spinal level. At segmental levels, the inhibitory action of large diameter cutaneous fibers is now well established. The action of fine fibers seems also to be inhibitory. Descending influences are exerted from the periaqueductal gray matter and the ventromedial medulla (mainly the nucleus raphe magnus). They are sustained by serotoninergic and noradrenergic mechanisms and they involve to a lesser extent the endogenous opioids. The physiological function of these descending systems is still sharply discussed.
Afferent Pathways↗
Spontaneous and evoked release of methionine-enkephalin-like material from the rat spinal cord in vivo.
In vivo perfusion of the subarachnoid space with an artificial cerebrospinal fluid (CSF) in paralyzed halothane-anesthetized rats allowed the collection of methionine-enkephalin (Met-Enk)-like material (MELM) released from the spinal cord. Bio-Gel P2 chromatography and high-performance liquid chromatography showed that 65% of this material corresponded to authentic Met-Enk. Under resting conditions, about 1 pg of MELM per minute was regularly released for at least 3 h; for Met-Enk, this value corresponded to a fractional rate constant of 0.002% (i.e. tissue content of the pentapeptide which was released per minute from the whole spinal cord). Perfusion with K+-enriched (40-60 mM) CSF resulted in a marked enhancement (+ 150-200%) of spinal MELM release. Similarly, calibrated pinches of the muzzle and i.p. administration of acetic acid, two strong noxious stimuli in awake animals, induced a significant increase (+ 75-150%) in spinal MELM release. In contrast, pinches applied to the tail did not enhance but instead slightly reduced (-35%) MELM release from the rat spinal cord. These data suggest that mechanisms other than segmental controls could be involved in the activation of spinal enkephalinergic neurons by some nociceptive stimuli.
Animals↗
Ultrastructural analysis of the terminals of various somatosensory pathways in the ventrobasal complex of the rat thalamus: an electron-microscopic study using wheatgerm agglutinin conjugated to horseradish peroxidase as an axonal tracer.
We used wheatgerm agglutinin conjugated to horseradish peroxidase (WGA:HRP) as an anterograde tracer to label the terminals of the lemniscal, spinothalamic, and trigeminothalamic pathways in the ventrobasal complex of the rat thalamus (VB). The use of benzidine dihydrochloride (BDHC) as the chromogen allowed us to view the labeled profiles with the electron microscope and permitted us to compare the morphology of the terminals from the various pathways. We found that all the labeled somatosensory pathways terminate in the VB in the form of large terminals that contain round synaptic vesicles and make numerous asymmetrical synaptic contacts, usually with dendritic protrusions and proximal dendrites. The present results demonstrate that pathways conveying noxious and non-noxious somatosensory information terminate upon thalamic neurons with synaptic terminals having similar morphological features.
Afferent Pathways↗
[Morphological changes of the terminations of afferent pathways in a neurodegenerative lesion induced by kainic acid].
30 days after kainic acid injection into the rat ventrobasal thalamus, lemniscal afferents were labeled using wheat-germ agglutinin conjugated to HRP. They appeared considerably swollen in the area where neuronal post-synaptic targets had been eliminated. Electron microscopic analysis of the lesioned tissue revealed the presence of large profiles containing numerous organelles, particularly smooth endoplasmic reticulum, and giving rise to thin excrescences filled with neurofilaments. Since these morphological features are typical of regenerating "growth cones", we conclude that afferent terminals deprived of their post-synaptic targets undergo morphological changes preparing them for new synapses.
Afferent Pathways↗
A reinvestigation of the analgesic effects induced by stimulation of the periaqueductal gray matter in the rat. I. The production of behavioral side effects together with analgesia.
It has been shown that stimulation-produced-analgesia (SPA) in the cat elicited from the periaqueductal gray matter (PAG) is obtained from sites located in the ventral part, particularly the dorsal raphé nucleus (DRN). These data contrast with the numerous studies performed in the rat in which efficient sites seem widely distributed throughout the PAG. These discrepancies led us to reinvestigate SPA from PAG and adjacent structures in the rat. Central stimulation was delivered through bipolar concentric electrodes (one for each animal). Analgesia was evaluated (before and during central stimulation) by measuring the modification in the vocalization threshold induced by electrical tail shocks or by considering the reaction of the animal to pinch. In contrast with the majority of previous studies, these experiments were performed on the totally freely-moving rat. The most striking result was that, in order to obtain analgesia from all regions of the PAG, it was necessary to apply intensities of central stimulation which also triggered other strong behavioral reactions. With intensities of PAG stimulation which did not induce such side effects, very few effective analgesic sites were found (21/129 sites of which 14/83 were strictly located in the PAG). However, it was possible to define two 'pure analgesic regions', both located in the ventral PAG: one centered on the dorsomedial part of the DRN and the other one situated in the ventrolateral PAG. No modification of nociceptive thresholds was observed when stimulating the dorsal and dorsolateral parts of the PAG as well as structures adjacent to these regions; in some rats, an increase in pain reactivity was even noted. When the intensity of central stimulation (applied to the various parts of the PAG) was increased, some stereotyped 'behavioral responses' occurred depending on the location of the stimulation site: motor effects (gnawing, rotation or tremor) in the ventral PAG and aversive effects (flight, jumping and on occasions, distress vocalizations) in the dorsal, dorsolateral PAG and in the ventral region just surrounding the cerebral aqueduct. Under these conditions, analgesia was obtained from practically the entire PAG, the vocalization threshold being increased dramatically on occasions. It must be emphasized that antinociceptive effects associated with other obvious behavioral manifestations (aversive ones) were also obtained from sites located outside the PAG (colliculi and tectum adjacent to the dorsal and dorsolateral PAG).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
A reinvestigation of the analgesic effects induced by stimulation of the periaqueductal gray matter in the rat. II. Differential characteristics of the analgesia induced by ventral and dorsal PAG stimulation.
This study consists of a detailed analysis of the analgesic effects induced by stimulation of the various parts of the periaqueductal gray matter (PAG) in the freely moving rat. In order to characterize the analgesia, two criteria are considered: (1) the evaluation of the degree of analgesia and behavioral side effects evoked during central stimulation; and (2) the presence of post-effects. Central stimulation (50 Hz sine waves) was delivered via bipolar concentric electrodes and analgesia was quantified by the change in the vocalization threshold induced by electrical stimulation of the tail. Within the ventral PAG, the vocalization threshold increased gradually with the intensity of the central stimulation, the degree of analgesia generally being powerful. There was no relationship between the strength of the analgesic effects and the motor disturbances also produced by stimulation of this region. Antinociceptive effects generally disappeared when the stimulation ceased. Only when the intensity of the stimulation was strong enough to induce very powerful analgesic effects were post-stimulation analgesic effects noticed. Within the dorsal and dorsolateral PAG as well as in the ventral region just surrounding the aqueduct, analgesia appeared suddenly, was generally less pronounced and was always concomitant with strong aversive reactions. In contrast with the analgesia from the ventral PAG, marked post-effects were observed. These latter characteristics were also obtained from stimulation of regions located outside the PAG (colliculi, intercollicular commissure and tectum adjacent to the dorsolateral PAG) although these zones were not extensively studied. By consideration of various data in the literature, it is concluded from this study, which clearly distinguishes stimulation-produced-analgesia (SPA) from ventral PAG versus dorsal PAG, that analgesia induced from this midbrain area involves at least two different neuronal substrates. Whilst the ventral PAG seems to be more preferentially involved in pain modulation, the authenticity of 'analgesia' triggered by stimulation of aversive regions (which are widely spread over the PAG) is questioned and proposals to explain the simultaneous appearance of analgesic effects and aversion are considered.
Animals↗
Coerulear projections to the lateral diencephalon in the rat. An anatomical study using wheat-germ agglutinin conjugated to HRP.
The orthograde axonal transport of wheat-germ agglutinin conjugated to horseradish peroxidase has been used to define the projections of the locus coeruleus toward the lateral thalamic nuclei in the rat. These projections had been overlooked in studies using neuroanatomical tract tracing techniques, despite the demonstration of the presence of norepinephrine in the lateral thalamus using histofluorescence and immunocytochemical techniques. Results obtained confirm the presence of a rather dense network of coeruleo-thalamic afferents. Terminal fibers appear thin and contorted, which could explain previous negative results. These anatomical data underline the possible role of the locus coeruleus in the modulation of the various sensory systems at the thalamic level.
Afferent Pathways↗
Diencephalic connections of the raphé nuclei of the rat brainstem: an anatomical study with reference to the somatosensory system.
The present study was undertaken to analyse in detail the connections of the various raphé nuclei with thalamic structures. Micropipettes filled with an aqueous solution of wheat-germ agglutinin conjugated to horseradish peroxidase were used to produce small iontophoretic deposits restricted to the various raphé nuclei in male Sprague Dawley albino rats. Tetramethyl benzidine was used as a chromogen to reveal both fiber terminals anterogradely labelled and retrogradely filled neurons. A detailed discussion of the possible cases of artefactual labelling using this technique is given. The present study confirms the results obtained previously in the cat that indicate that the various raphé nuclei project to different areas of the diencephalon. Related to the somatosensory system, the B3 area (nucleus raphé magnus) projects to the nucleus submedius and anterior intralaminar nuclei known to receive spinothalamic inputs, but not to the ventrobasal complex. The distribution of afferents from this nucleus suggests an innervation primarily of thalamic structures involved in the somatosensory system. The nucleus raphé medianus projects to the ventrobasal complex and the nucleus submedius , but the fact that its projections are widespread, including all thalamic sensory "relay" nuclei and the entire nucleus reticularis thalami, suggests that it could participate in a "nonspecific" system of control of different sensory modalities. The nucleus raphé dorsalis generally does not project to the thalamic nuclei believed to be involved in the somatosensory system.
Animals↗
Projections from the periaqueductal gray matter to the B3 cellular area (nucleus raphe magnus and nucleus reticularis paragigantocellularis) as revealed by the retrograde transport of horseradish peroxidase in the rat.
Afferent projections from the periaqueductal gray matter (PAG) to the B3 region (nucleus raphe magnus, NRM; and nucleus reticularis paragigantocellularis, NPG) were examined by means of the horseradish peroxidase (HRP) method revealed by using the tetramethylbenzidine (TMB) procedure. Following iontophoretic injection of HRP into the B3 cellular area, numerous labeled neurons were found between the third oculomotor complex and the rostral part of the tegmental nucleus dorsalis of Gudden. The most densely labeled regions were the lateral parts of the dorsal raphe nucleus (wings of the DRN) and Hamilton's nucleus dorsalis of the PAG. Very few neurons were found within the medial part of the DRN. In contrast, results with control injections performed outside the B3 area gave a different distribution of labeled neurons. The functional significance of these connections, particularly those emanating from the wings of the DRN which represent new information, is briefly discussed with regard to mechanisms operative in the control of pain. Although the major PAG-B3 direct projections could underlie a role for the B3 area in PAG-induced analgesia, the comparison of our anatomical and behavioral results points out some problems. Indeed, there is no strict correlation between the location of stimulation sites which induce analgesia in the freely moving rats and the distribution within the PAG of B3 projections. These observations lead us to question the role of direct PAG-B3 connections in the antinociception induced by PAG stimulation and alternative hypotheses are proposed.
Analgesia↗
The effect of morphine on the potassium evoked release of tritiated 5-hydroxytryptamine from spinal cord slices in the rat.
The effect of morphine on the potassium (40 mM) evoked release of exogenous [3H]5-HT from slices of the dorsal spinal cord of the rat was studied. The effects of in vitro applied morphine on the slices were compared to those produced by systemic morphine applied to the animals before preparation of the slices. The in vitro application of morphine (10(-6) to 10(-5) M) did not affect the release of [3H]5-HT. By contrast, it was observed that the potassium evoked release of [3H]5-HT from the slices of the spinal cord of rats which had received 10 mg/kg s.c. of morphine 30 min beforehand was significantly increased. The effect of systemic morphine was dose-dependent (in the range of 1.5-10 mg/kg s.c.) and could be blocked by prior administration of naloxone (1 mg/kg i.m.) 2 min before the morphine. The acute administration of 10 mg/kg s.c. of morphine, which did not induce analgesia in rats rendered tolerant to morphine, did not modify the [3H]5-HT release. Higher doses of morphine, which have been shown to restore analgesia in these rats, induced an increase in the release which was significant for a dose of 100 mg/kg s.c. These results demonstrating a specific and dose-dependent increase in the potassium evoked release of [3H]5-HT from spinal dorsal cord slices after systemic administration of morphine, emphasize the role of serotonergic systems in such analgesia. The lack of effect of the drug directly applied in vitro favours a supraspinal site of action of the drug and is in good agreement with recent results in the literature.
Animals↗
Further evidence for a bidirectional effect of naloxone on the pain threshold in tolerant and non-tolerant arthritic rats.
In arthritic rats, low doses of naloxone induced powerful analgesic effects (as gauged by the vocalization threshold elicited by pressure on the paw) which were marked for 3 and 6 micrograms/kg IV, whereas high doses (1000 and 3000 micrograms/kg IV) induced hyperalgesia. This bidirectional effect persisted in arthritic rats rendered tolerant to morphine, but whereas the analgesic effects were suppressed or reduced, the hyperalgesic effects induced by the higher doses were unchanged. These results suggest that the analgesic and hyperalgesic effects might be mediated by different systems.
Animals↗