Age-related changes in dopaminergic and serotonergic indices in the rat forebrain.

Age-related changes in the content of dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in anterior cerebral cortex, hippocampus and striatum of the rat have been investigated using HPLC with electrochemical detection. A significant decrease in HVA was observed in the striatum and hippocampus of the aged (27 months) animals, as compared to the controls (2.4 to 2.6 months). A significant decrease in DA levels was also observed in the hippocampus but not in the striatum. In contrast, the level of DA in the cerebral cortex was markedly increased in the aged animals. A concomitant increase in 3-MT level was observed. Finally the level of 5-HIAA was significantly increased in striatum and hippocampus.

Differential time course and spatial expression of Fos, Jun, and Krox-24 proteins in spinal cord of rats undergoing subacute or chronic somatic inflammation.

We have used the evoked expression of both immediate early gene (IEG)-encoded proteins (Krox-24, c-Fos, Fos B, Jun D, Jun B, c-Jun), and dynorphin to monitor sensory processing in the spinal cords of rats undergoing subacute or chronic somatic inflammation (i.e., subcutaneous inflammation of the plantar foot and monoarthritis, respectively). Behavioral and immunocytochemical approaches were conducted in parallel up to 15 weeks postinjection in order to detect possible relationships between clinical evolution and spatiotemporal pattern of IEG-encoded protein expression. Each disease had specific characteristics both in terms of their clinical evolution and pattern of evoked protein expression. All IEG proteins were expressed in both cases. Most of the staining was observed in both the superficial layers of the dorsal horn and deep dorsal horn (laminae V-VII and X). Monoarthritis was distinguished by a high level of total protein expression. Staining was especially dense in the deep dorsal horn. More labelled cells were observed at 1-2 days and at 2 weeks postinjection, corresponding to the initiation and progressive phases of the disease, respectively. Subcutaneous inflammation was characterized by a moderate level of total IEG expression. More labelled cells were observed in the first day following injection. It is the relative degree of expression of each IEG-encoded protein with regard to the others that characterized the progression of the diseases. Early stages of the diseases coincided with the expression of all Fos and Jun proteins, while late stages showed an increase in Jun D and Fos B involvement; Krox-24 was induced mostly during the early phases and/or periods of paroxysm of the diseases. Persistent stimulation was characterized by a predominant expression in deep versus superficial layers of the dorsal horn. Evoked expression of c-Jun in motoneurons was only observed in monoarthritis. The peak of dynorphin expression was late in regard to both the induction of inflammation and period of maximal IEG-encoded protein expression. The present work indicates that the neural processing that takes place during progression of these diseases can be monitored well at the spinal cord level by using the expression of an array of IEG-encoded proteins. Study of long term evolutive diseases and especially those that evolve into chronicity can largely benefit from such an approach.

Relation of sex and ageing to serotonin metabolism in rats.

The present study deals with serotonin (5-HT) metabolism at the central and peripheral levels in young, middle-aged and old male and female rats. From middle age, the level of endogenous 5-HT and the uptake of [14C] 5-HT were higher in the platelets of female rats than in those of male rats. By contrast, the retention of [14C] 5-HT by the platelets of male rats decreased after middle age. The 5-hydroxyindoleacetic acid (5-HIAA) level in plasma was lower in males than in females, and this level increased significantly with age in males. In brain, the tryptophan level decreased significantly with age in male rats, while the 5-HT level increased in males as well as females. The brain 5-HIAA level increased significantly with age in male rats. These results confirm that 5-HT metabolism is modified during the ageing process in rats, and that several factors may be involved in this modification.

Hindbrain structures involved in pain processing as revealed by the expression of c-Fos and other immediate early gene proteins.

We have used the evoked expression of the immediate early gene-encoded proteins (c-Fos, Fos B, Jun B, Jun D, c-Jun and Krox-24) to monitor sensory processing in the hindbrain structures of rats undergoing somatic inflammation. Experiments were performed on freely moving animals that did not experience constraints other than those imposed by the disease itself. Local injections of chemicals were used to cause subcutaneous inflammation of the plantar foot or monoarthritis by intracapsular injection. Labelling was studied at survival times that corresponded either to the time points of maximum labelling in the spinal cord (4 h for the subcutaneous model, 24 h and two weeks for the monoarthritis model) or at survival times that corresponded to the chronic phase of monoarthritis evolution (six, nine and 15 weeks). Controls consisted of freely moving, unstimulated animals. Basal expression was observed for all immediate early genes and in a variety of structures, but always remained moderate. All immediate early gene-encoded protein expressions except c-Jun were evoked, but except for c-Fos, and to a lesser extent Jun D, intensities of staining always remained faint. The following results will be mainly based on c-Fos expression, as this protein proved to be the most effective marker for all the survival times studied. Somatic pain evoked c-Fos expression in a subset of discrete subregions of both the caudal medulla oblongata and transitional areas of the pontomesencephalic junction. In the caudal medulla oblongata, structures involved were the caudal intermediate reticular nucleus, the subnucleus reticularis dorsalis, the ventrolateral reticular formation and the lateral paragigantocellular nucleus. Structures involved at the pontomesencephalic junction level mostly included the superior and dorsal lateral subnuclei of the parabrachial area, the nucleus cuneiformis and the most caudal portions of the lateral central gray, also including the laterodorsal tegmental nucleus; labelling in other lateral subnuclei of the parabrachial area always remained moderate. Staining in the caudal reticular areas was evident only at short survival times (4 and 24 h survival times in subcutaneous and monoarthritis models, respectively). Staining in nuclei of the pontomesencephalic junction was evident in all cases except for the very long survival periods (six to 15 weeks) of monoarthritis. In all cases staining was bilateral with contralateral predominance with regard to the stimulated limb. The present work demonstrates that hindbrain structures involved in somatic pain processing can be effectively identified in behaving animals and that c-Fos is the most reliable activity marker in this case.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in total and free tryptophan levels in serum following acute morphine administration in arthritic rats.

In 'arthritic' rats a decrease in total tryptophan and an increase in free tryptophan levels was observed in serum after morphine administration (10 mg kg, s.c.). These changes were maximum within 15 and 30 min after injection. A decrease in total and an increase in free tryptophan levels in serum were observed 30 min after naloxone administration (1 mg/kg, i.m.). An increase in tryptophan and 5-hydroxyindoleacetic acid levels was also observed in the brain after morphine and naloxone. These observations suggest that the rise in 5-hydroxytryptamine synthesis provoked by morphine may be partly related to an increase in the availability of tryptophan from blood. However, the analgesia induced by the opiate appears unlikely to be directly related to this effect.

Sympathectomy does not modify the levels of dopa or dopamine in the rat dorsal root ganglion.

In the present study we report on the levels of dihydroxyphenylalanine (DOPA), dopamine and their metabolites, 3-O-methyl-DOPA, homovanillic acid and dihydroxyphenylacetic acid, in the dorsal root ganglion (DRG) where dopaminergic sensory neurons have recently been identified. HPLC with electrochemical detection was used. Chemical sympathectomy, induced by daily injection of 30 mg/kg/sc of guanethidine over 4 days, did not modify these levels. DOPA, dopamine and their metabolites were also detected in the dorsal root in both intact and sympathectomized rats. The present results show that in the DRG, DOPA and dopamine do not derive from sympathetic nerves, and agree with previous reports suggesting that there is a peripheral dopaminergic sensory innervation. In addition the identification of 3-O-methylDOPA, the extraneuronal metabolite of DOPA is not only the precursor of dopamine in the DRG but may be released from DRG cells. The high 3-O-methyl-DOPA/DOPA ratio found in the DRG and the dorsal root suggests that DOPA could play a role as neurotransmitter or modulator in the peripheral sensory innervation, as it has been proposed for the central nervous system and the sympathetic system.

A new microdissection technique for regional biochemical analysis of the rat spinal cord: serotonin, norepinephrine, dopamine and uric acid.

This report described a new microdissection procedure to evaluate the regional distribution of neuromediators in the rat spinal cord. Different segments are first divided into sagittal slices. From these, different grey and white matter regions can be microdissected. This permits selective biochemical measurements in different laminae, including the area around the central canal. White and grey matter can also be differentially analysed. Using HPLC with electrochemical detection, we report on the regional analysis of biogenic amines as well as uric acid. An increase in 5-hydroxytryptamine (5-HT) levels was observed from cervical to lumbar segments. 5-HT levels were highest in the motoneurone samples (lamina IX) of the lumbar cord. The next highest levels were found in lamina X, followed by the intermediate grey matter laminae and the dorsal horn. Small amounts of 5-HT were detected in the white matter. Interestingly, the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT was greatest in the white matter and least in the motoneurone sample. Norepinephrine (NE) levels were higher in the thoracic than in the cervical or the lumbar cord. The highest levels were found in the lamina X in thoracic segments. With this exception, no marked laminar difference in NE levels was observed. Dopamine (DA) levels were highest in the dorsal horn of the cervical and the thoracic cord, the next highest levels were found in the intermediate grey matter and lamina X in the same segments. The distribution of uric acid (UA) was comparable to that of NE: UA levels were highest in the thoracic cord, but no marked laminar difference was observed. On the other hand, UA levels in white matter generally exceeded those in the grey matter. These data indicate the value of a sagittal regional microdissection of the spinal cord. The ability to separately analyse different laminae of the cord (as well as differentiating grey and white matter) should prove useful in future studies of experimentally evoked changes in neurotransmitters within functionally distinct regions of the spinal cord.

Changes in brain and spinal tryptophan and 5-hydroxyindoleacetic acid levels following acute morphine administration in normal and arthritic rats.

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats. (1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord. (2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine. The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activation of the ascending pathway previously demonstrated by several authors and confirmed here.

Increase in 5-HT synthesis in the dorsal part of the spinal cord, induced by a nociceptive stimulus: blockade by morphine.

The effects of a nociceptive peripheral stimulus and/or morphine upon endogenous tryptophan levels (TRP), specific activity of tryptophan (S.A. of TRP) and serotonin (5-HT) synthesis in the dorsal and ventral spinal cord, the brainstem and the forebrain were investigated in anaesthetized rats. Whereas endogenous TRP and S.A. of TRP were not found to be affected by any of the manipulations described below, 5-HT synthesis was markedly altered. The application of a prolonged and intense nociceptive electrical stimulus to the tail induced a rise in 5-HT synthesis which was dependent on the part of the CNS considered, with the dorsal cord being the most sensitive (25%), the ventral cord and the brainstem being effected to a lesser extent (14% and 16% respectively), and the forebrain not being affected significantly. By contrast, the application of a prolonged and innocuous electrical stimulus on the tail was not followed by any detectable changes in 5-HT synthesis. Morphine administration (1 mg/kg; i.v.) did not significantly alter 5-HT synthesis in the four CNS regions considered. Nevertheless, the same morphine dose did induce a highly significant (P less than 0.005) reduction in the increase in 5-HT synthesis induced by the nociceptive stimulus, both in the dorsal cord and in the brainstem. Such an effect was not seen in the ventral cord. The specificity of these morphine effects was demonstrated by their naloxone reversibility; on the other hand, naloxone alone failed to modify the stimulus-induced increase in 5-HT synthesis seen in the dorsal cord and the brainstem. The results, particularly those concerning the dorsal cord, are discussed with reference to pain mechanisms and morphine analgesia. They suggest that peripheral nociceptive messages induce an increased activity in some bulbo-spinal 5-HT pathways and that a low dose of morphine can counteract such an effect. It is proposed that exogenous opiates exert a complex regulation of bulbo-spinal 5-HT pathways. Functional significances of these processes are discussed.

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.

Effect of acute administration of morphine on newly synthesized 5-hydroxytryptamine in spinal cord of the rat.

The effect of morphine (10 mg/kg, s.c.) on the rate of [3H]5-HT synthesis in brain and spinal cord following intravenous injection of [2H]tryptophan was studied in the rat. (1) In the spinal cord morphine induced an increase in [3H]TRP uptake which was significant 30 and 60 min after the injection, and a clear enhancement of the formation of [3H]5-HT which was significant 15 min after the injection and which peaked at 30 min. In the forebrain, the increase in [3H]TRP accumulation was significant as early as 15 min after morphine. At this time, the rate of 5-HT synthesis was not modified, but it was significantly increased 30 and 60 min after the injection. (2) Increases in [3H]5-HT synthesis rate were suppressed by naloxone (1 mg/kg, i.m.). However this narcotic antagonist did not significantly reduce the increased accumulation of [3H]TRP in brain and spinal cord due to morphine treatment. These results demonstrate that morphine induces a fast and marked increase in 5-HT synthesis, and suggest that this increase is only partly related to an increase in the availability of tryptophan to the central nervous system. These results are in good agreement with recent investigations showing the involvement of the raphe-spinal system in morphine analgesia.

Unilateral joint inflammation induces bilateral and time-dependent changes in neuropeptide FF binding in the superficial dorsal horn of the rat spinal cord: implication of supraspinal descending systems.

Using quantitative autoradiography, the effects of acute and chronic inflammation on specific 125I-1DMethyl-FLFQPQRFamide binding were investigated in the rat spinal cord dorsal horn superficial layers, at 6 and 24 h and 2, 4, 6 and 12 weeks after induction of monoarthritis produced by injection of killed Mycobacterium butyricum suspended in Freund adjuvant in one tibio-tarsal joint. Six hours after monoarthritis induction, no modification in specific 125I-1DMethyl-FLFQPQRFamide binding was observed, whereas a significant bilateral increase occurred after 24 h and 2 weeks in L4/L5 dorsal horns, with a return to control values at 4, 6 and 12 weeks. Specific 125I-1DMethyl-FLFQPQRFamide binding was also investigated 24 h after monoarthritis induction in rats submitted 4 days before the induction to spinal cord lesions at the thoracic level (T9-T10). Hemisection of the spinal cord contralateral to the affected ankle prevented the transient bilateral increase in specific 125I-1DMethyl-FLFQPQRFamide binding, whereas total spinal cord section induced a significant bilateral decrease. All of these modifications were restricted to the spinal segments receiving afferent input from the arthritic ankle (L4/L5); no modifications were found at the levels L1 or C6-C8. These data suggest that FLFQPQRFamide is involved in spinal nociceptive processing during sustained peripheral nociceptor activation. The effects of spinal cord lesions in monoarthritic rats indicate that the modifications seen in the FLFQPQRFamide system activity, during sustained peripheral inflammation, depend on afferent fiber activation as well as on supraspinal controls.

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.

The relationship between morphine analgesia and the activity of bulbo-spinal serotonergic system as studied by tolerance phenomenon.

The effect of various doses of acute morphine on both analgesia and 5-hydroxytryptamine (5-HT) synthesis in the brain and the spinal cord has been studied in rats rendered tolerant by chronic administration of the analgesic. In morphine-tolerant rats, the incorporation of tritiated-L-tryptophan (TRP) in the brain and the spinal cord was higher than in non-tolerant rats, but there was no significant difference in the synthesis rate of the newly formed 5-HT between the two groups. An acute dose of morphine (10 mg/kg) which induced a powerful analgesia and a large increase in 5-HT synthesis in non-tolerant rats, did not produce analgesia nor changes in 5-HT synthesis in tolerant rats. Higher acute doses of morphine which restored analgesia in tolerant rats, induced a discrete increase in [3H]TRP incorporation and a marked increase in 5-HT synthesis in the spinal cord of these animals. The same doses significantly increased [3H]TRP incorporation in the forebrain but did not modify 5-HT synthesis. These results show that tolerance to morphine is associated with a decrease in the effects of the drug on 5-HT synthesis in the spinal cord and the brain and tend further support to the hypothesis that an enhancement of 5-HT synthesis in the spinal cord, induced independently of modifications of the availability of TRP, is associated with the analgesic effect of morphine.

Morphine analgesia and newly synthesized 5-hydroxytryptamine in the dorsal and the ventral halves of the spinal cord of the rat.

In the rat, morphine (5 mg/kg, s.c.) induced an increase in 5-hydroxytryptamine (5-HT) synthesis in the spinal cord. These effects appeared with a shorter latency and are much more marked in the dorsal half than in the ventral half. Although the increase in the dorsal half was slightly delayed by comparison with the onset of the analgesic effect the maxima for both phenomena were simultaneous. The role of the bulbo-spinal serotonergic system in morphine analgesia is discussed.

Simultaneous measurements of tryptophan and its metabolites, kynurenine and serotonin, in the superficial layers of the spinal dorsal horn. A study in normal and arthritic rats.

It has been demonstrated that 5-hydroxytryptamine (5-HT) is not the only neuroactive metabolite of tryptophan (TRP) in the CNS. The presence of kynurenine (KYN) and its metabolites has been reported in the brain of several mammalian species and the neuroactive properties of these compounds are now well established. In the present study, we report the identification of KYN in the superficial layers of the rat spinal dorsal horn. KYN was measured simultaneously with TRP. 5-hydroxytryptophan, 5-HT, 5-hydroxyindoleacetic acid and 5-HT-O-sulfate by means of liquid chromatography with coulometric electrode array detection. The results observed in the normal rat and in an animal model of persistent pain, the arthritic rat, are discussed in view of the hypothesis relating to the involvement of the bulbospinal serotonergic system in pain mechanisms and of the possible participation of KYN and its metabolites in these mechanisms.

Absence of long-term changes in biochemical markers of monoaminergic systems afferent to the excitotoxically neuron-depleted somatosensory thalamus.

In a previous study, it was shown that, one month after kainic acid (KA) injection into the thalamus, afferents deprived of postsynaptic target neurons exhibit structural alteration, including the loss of synaptic vesicles. The present study was undertaken to determine whether these long-term morphological changes were associated with changes in biochemical markers of monoaminergic pathways. In situ injection of KA was performed into the right ventrobasal complex of the rat thalamus (VB). Protein content and total amount of norepinephrine, dopamine, 5-hydroxytryptamine and 5-hydroxyindolacetic acid were analyzed in the lesioned area one, two, three and four months after injection using high-performance liquid chromatography and electrochemical detection. The results were compared to those obtained in an equal volume of tissue dissected out from the opposite (intact) VB. Protein content per unit volume decreased progressively to 50% of control in the neuron-depleted area. In contrast, whatever the amine considered, its total amount remained unaltered up to 4 months after the excitotoxic lesion. 5-hydroxyindolacetic acid was also unchanged 4 months after lesion. This study suggests that (i) the quantity of monoamines in afferents to the rat VB does not depend upon the presence of postsynaptic target neurons, (ii) a non-vesicular storage compartment may compensate the loss of synaptic vesicles in afferent fibers to the lesioned area.

Monoarthritis induces complex changes in mu-, delta- and kappa-opioid binding sites in the superficial dorsal horn of the rat spinal cord.

Recently, an experimental model of monoarthritis was described in the rat induced by injection with Freund's adjuvant of the tibio-tarsal joint of one hindlimb. After injection, the clinical and behavioural signs of arthritis are stable from weeks 2 to 6 post-injection. Our purpose was to study the regulation of mu-, delta- and kappa-opioid binding sites in the superficial layers (laminae I-II) of the lumbar and cervical enlargements of the spinal cord 2, 4 and 6 weeks post-injection. Using quantitative receptor autoradiography and highly selective opioid ligands, we found complex changes consisting of a bilateral increase in specific [3H]DAMGO (Tyr*-D-Ala-Gly-NMe-Phe-Gly-ol) and [3H]pCl-DPDPE (Tyr*-D-Pen-Gly-Cl-Phe-D-Pen) binding at 2 weeks post-injection and a bilateral decrease in [3H]U-69593 ((5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl]) specific binding at 4 weeks post-injection. These changes were restricted to the lumbar level. At 6 weeks post-injection, there was a bilateral increase in [3H]pCl-DPDPE specific binding at both lumbar and cervical levels. Altogether, these results suggest that, after probable local changes in endogenous opioid peptides, the three types of opioid binding sites are differentially involved in the development of the pathological process. These results contrast with the lack of significant modification in mu-, delta- and kappa-opioid binding classically reported at various levels of the spinal cord in polyarthritic rats at 3 weeks post-injection and verified for 2, 4 and 6 weeks post-injection in the present study.

Effect of deafferentation on the levels of uric acid in the spinal cord of the rat.

In previous studies we reported that the rat spinal cord contains relatively high levels of uric acid and that the levels in a rat model of bilateral chronic pain, experimental adjuvant arthritis. In this report we evaluate the changes in UA in the unilaterally deafferented rat, a preparation which has also been used to study chronic pain. Uric acid was measured by high-pressure liquid chromatography with electrochemical detection in the spinal cord of rats that underwent unilateral, multiple cervical dorsal rhizotomy. Compared to control and sham-operated rats, there was a significant increase in the level of uric acid in the dorsal quadrant of the spinal cord ipsilateral to the dorsal rhizotomy. This increase was present at 1 and 4 weeks after surgery. At 1 week, we also observed a small but statistically insignificant increase in uric acid levels in the dorsal quadrant contralateral to the deafferentation and in sham-operated rats. Four weeks after surgery the levels of UA in all regions except for the deafferented dorsal quadrant returned to normal. The possibility was raised that the changes in uric acid reflect an increase in purinergic metabolism in the spinal cord secondary to the increased activity of the dorsal horn neurons that occurs with deafferentation.

Decreased cerebrospinal fluid neuropeptide-converting enzyme activity in monoarthritic rats.

The activity in rat cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE) was determined in control animals and in rats with monoarthritis. Enzymatic activities were measured with specific radioimmunoassays toward the N-terminal products Leu-enkephalin-Arg6 and substance P1-7, respectively. A monoarthritis stable during weeks 2-6 post-injection was induced by injection (0.05 ml) into one joint with Freund's adjuvant. Both SPE and DCE were significantly decreased 15 days after the intraarticular injection. Despite the degree of arthritis that was sustained equally at four weeks after inoculation, both DCE and SPE were back to control levels at that time. It can therefore be concluded that arthritis from a single joint is sufficient to elicit changes in CSF convertase activities, and that these effects disappear between 2 and 4 weeks after injection, although the arthritis persists.