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Biomedical subjects

J M Besson

Publications and source records attributed to J M Besson.

At least 37 records · Page 2Linked to original sources
PubMed1998

UP 202-56, an adenosine analogue, selectively acts via A1 receptors to significantly decrease noxiously-evoked spinal c-Fos protein expression.

The effects of oral administration of UP 202-56, an adenosine analogue, were assessed on carrageenan-induced spinal c-Fos protein expression and peripheral oedema. Three hours after intraplantar injection of carrageenan (6 mg/150 microl of saline), in awake rats, numerous c-Fos-like immunoreactive (c-Fos-LI) neurons in the dorsal horn of L4-L5 lumbar segments of the spinal cord (191 +/- 8; 184 +/- 10; 205 +/- 7 c-Fos-LI neurons per 40 microm section, for carrageenan controls in three experimental series performed in this study, respectively) and an extensive peripheral oedema were observed. Oral UP 202-56 (10, 30 or 50 mg/kg) dose-dependently reduced the number of carrageenan-induced c-Fos-LI neurons (r = 0.931. P < 0.0001), with the highest dose of UP 202-56 producing 72 +/- 4% reduction of the total number of carrageenan-induced spinal c-Fos-LI neurons, and 12 +/- 3% and 33 +/- 6% of reduction of control carrageenan oedema at paw and ankle levels, respectively. DPCPX (1 mg/kg i.p.), a selective adenosine A1 receptor antagonist, which injected alone had no effect on carrageenan-induced spinal c-Fos expression and peripheral oedema, blocked the effects of UP 202-56 (30 mg/kg p.o.) on the number of carrageenan-induced c-Fos-LI neurons. In addition, DPCPX did not modify the effects of UP 202-56 on carrageenan-induced peripheral oedema. DMPX (1 mg/kg i.p.), a somewhat selective adenosine A2 receptor antagonist, which injected alone had no significant effect on carrageenan-induced spinal c-Fos protein expression and peripheral oedema, did not influence the effects of UP 202-56 (30 mg/kg p.o.) on both carrageenan-induced spinal c-Fos expression and peripheral oedema. Our results demonstrate that UP 202-56 dose-dependently reduced the spinal c-Fos protein expression in carrageenan model of inflammatory pain. The ability of DPCPX to block the effect of UP 202-56, in contrast to the lack of effect of DMPX, increased evidence for a predominant role of adenosine A1 receptors activation in the mechanism of action of UP 202-56. These results increase evidence for a role of adenosine in the modulation of nociceptive transmission and support the antinociceptive action of adenosine analogues, such as UP 202-56, in inflammatory pain processes.

Adenosine↗
PubMed1998

Peripheral and/or central effects of racemic-, S(+)- and R(-)-flurbiprofen on inflammatory nociceptive processes: a c-Fos protein study in the rat spinal cord.

1. We have evaluated the effects of intravenous or intraplantar racemic-, S(+)- and R(-)-flurbiprofen on both the carrageenan-evoked peripheral oedema and spinal c-Fos immunoreactivity, an indirect index of neurons involved in spinal nociceptive processes. 2. Three hours after intraplantar injection of carrageenan (6 mg in 150 microl of saline) in awake rats, a peripheral oedema and numerous c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4 L5 segments were observed. c-Fos-LI neurons were essentially located in the superficial (I-II) and deep (V-VI) laminae of the dorsal horn. 3. Intravenous racemic-flurbiprofen (0.3, 3 and 9 mg kg(-1)) dose-relatedly reduced the carrageenan-evoked oedema and spinal c-Fos expression (r=0.64, r=0.88 and r=0.84 for paw diameter, ankle diameter and number of c-Fos-LI neurons; P<0.05. P<0.001 and P<0.001 respectively). 4. Similar effects to those of intravenous racemic-flurbiprofen were obtained with intravenous S(+)-flurbiprofen (0.3, 3 and 9 mg kg(-1)) which dose-relatedly reduced the number of c-Fos-LI neurons (r=0.69, P<0.01) and diameters of paw and ankle (r=0.56 and r=0.52 respectively, P<0.05 for both). 5. For the dose of 0.3 mg kg(-1) i.v., R(-)-flurbiprofen did not modify the number of c-Fos-LI neurons and produced a weak reduction of oedema at only the ankle level (23+/-12% reduction, P<0.05). However, a ten times higher dose of R(-)-flurbiprofen (3 mg kg(-1) i.v.) was necessary to obtain effects comparable to those of S(+)- or racemic-flurbiprofen (0.3 mg kg(-1) i.v.). 6. Intraplantar racemic-flurbiprofen (1, 10 and 30 microg) dose-relatedly reduced the carrageenan-enhanced ankle diameter (r=0.81, P<0.001) and the number of c-Fos-LI neurons in L4-L5 segments (r=0.83, P<0.001). with a 60+/-3% reduction of the number of c-Fos-LI neurons (P<0.001), and 30+/-3 and 67+/-7% reduction of paw and ankle diameter respectively (P<0.001 for both) for the dose of 30 microg. 7. For intraplantar S(+)-flurbiprofen (1, 10 and 30 microg) the dose-related effects (r=0.77, r=0.60 and r=0.59 for c-Fos-LI neurons, paw and ankle diameters respectively, P<0.001, P<0.01 and P<0.01) were similar to those of racemic-flurbiprofen. In contrast, intraplantar R(-)-flurbiprofen (1, 10 and 30 microg) did not have detectable effects on all studied parameters. 8. The present study provides clear evidence for potent anti-inflammatory and antinociceptive effects of both intravenous or intraplantar racemic- and S(+)-flurbiprofen. These results further demonstrate marked anti-inflammatory and antinociceptive effects of intravenous, but not intraplantar, R(-)-flurbiprofen. These results suggest that the main site of action of racemic- and S(+ )-flurbiprofen is in the periphery and indicate that the site of action of R(-)-flurbiprofen is mainly of central origin.

Analgesics↗
PubMed1997

Nitric oxide (NO): in vivo electrochemical monitoring in the dorsal horn of the spinal cord of the rat.

NO synthase (NOS) is largely distributed in the superficial and deep laminae of the dorsal horn as well as in dorsal root ganglion cells. It has been proposed that nitric oxide (NO) participates in the transmission of sustained, and possibly brief, nociceptive, inputs at the spinal level. The aim of this study was to check the ability of in vivo electrochemical monitoring of NO within the dorsal horn of the lumbar spinal cord (L3-L4 level) of chloral hydrate anesthetized or decerebrated spinalized rats. 30 microm diameter and 450 microm length treated carbon fiber electrodes coated with nickel(II) tetrakis (3-methoxy-4-hydroxy-phenyl) porphyrine and NafionR, and associated with differential normal pulse voltammetry, gave a peak of oxidation current around 650 mV (vs. Ag-AgCl) in vitro in NO solutions between 0.125 and 1.25 microM. In vivo, a 650 mV peak appeared which was stable (recording interval 2 min) for up to 3 h (+/-6%). Comparison between in vitro calibration and in vivo voltammograms gave an estimated in vivo extracellular concentration of 0.50 microM. In vivo, peaks decreased by 95% at 90 min and for up to 3 h after an i.p. injection of 100 mg/kg of the NOS inhibitor (NOSI) L-arginine-p-nitroanilide (L-ANA). At the same dose i.p., N(G)-nitro-L-arginine methyl ester (L-NAME) was almost ineffective after 90 min in animals paralyzed with pancuronium bromate or gallamine trethiodide. However, in non-curarized decerebrated spinalized animals, L-NAME depressed the voltammograms by 36% at 90 min. S-Ethylthiourea (80 mg/kg i.p.), also decreased the voltammograms by 45% at 140 min, and finally, 7-nitroindazole (7-NI, 90 mg/kg i.p), induced a important decrease of the 650 mV peak (23% of control) at 120 min. These results are in agreement with biochemical data showing the decrease of NOS activity within the lumbar spinal cord by L-NAME (45% of control at 90 min) and 7-NI (20% of control at 90 min). The NO donor hydroxylamine (30 mg/kg i.p.) significantly increased the peaks (140% at 90 min), and sodium nitroprusside (SNP, 20 mM) when directly superfused upon the spinal cord (200-300 microl min(-1)) induced a large increase in the peak (300% at 90 min). Moreover, SNP 60 min after L-ANA, or 90 min after L-NAME, rapidly restored the 650 mV peak up to control values. These results demonstrate the validity of electrochemical monitoring of NO within the dorsal horn of the spinal cord. The in vivo electrochemical detection of NO is in progress to study the implication of this messenger in the transmission of nociceptive messages at the spinal level.

Anesthesia, General↗
PubMed1997

Further evidence for the involvement of the spinoparabrachial pathway in nociceptive processes: a c-Fos study in the rat.

We have analysed in briefly anaesthetised rats (1% halothane for 18 minutes) the effects of innocuous and noxious heat, applied to the hindpaw, on evoked c-Fos immunoreactivity at the levels of the parabrachial area (PB), spinal cord, and nucleus of the solitary tract (NTS). After anaesthesia recovery, animals were left to move freely for 2 hours. At the spinal level, c-Fos was expressed primarily in the ipsilateral superficial laminae, increasing with the applied temperatures in a dependent manner in the noxious range (correlation coefficient r = 0.954, n = 20). At the NTS level, no noxiously evoked c-Fos expression was observed. At the PB level, c-Fos was expressed preferentially contralaterally, increasing with the applied temperatures in a dependent manner in the noxious range (r = 0.971, n = 25). The maximum expression was observed in the outer portion of the external lateral, the lateral crescent, and the superior lateral subnuclei around the pontomesencephalic junction. This was congruent with the densest supraspinal projection of lamina I neurones of the dorsal horn. Labelling in the PB area was highly correlated (r = 0.936, n = 20) with labelling in the superficial laminae. We conclude that, under our experimental procedures, noxious heat-induced c-Fos expression at the PB level depends on the intensity of the noxious stimulation. These data further support the relevance of the recently described spino-PB pain pathway. Because of their location, the Fos-immunoreactive neurones observed in the pontine and the mesencephalic divisions of the PB area were likely PB-amygdaloid and PB-hypothalamic nociceptive neurones, respectively.

Animals↗
PubMed1997

Organization of efferent projections from the parabrachial area to the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat.

The organization of projections from the parabrachial (PB) area to the hypothalamus was studied in the rat by using microinjections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into subregions of the PB area. The present study is a follow-up of two former studies (Bernard et al. [1993] J. Comp. Neurol. 329:201-229; Aldén et al. [1994] J. Comp. Neurol. 341:289-314) that examined PB projections onto the amygdala and the bed nucleus of the stria terminalis. The results demonstrate that 1) the mesencephalic PB region, centered in the lateral portion of the superior lateral subnucleus projects extremely densely to almost the entire dorsomedial subdivision of the ipsilateral ventromedial hypothalamic nucleus; 2) the mesencephalic PB region, located in the medial portion of the superior lateral subnucleus and weakly overflowing into the rostralmost dorsal lateral pontine subnucleus, projects densely to the retrochiasmatic area and, to a lesser extent, to the ipsilateral ventromedial nucleus of the hypothalamus; 3) the PB region, including the central lateral, a portion of the superior lateral, and the outer external lateral subnuclei, projects densely to the ipsilateral median, anteroventral, and periventricular preoptic hypothalamic nuclei and projects more weakly to the dorsal border of the paraventricular nucleus (PVN). No consistent projection was found in the magnocellular PVN. All of these PB regions also project diffusely to the dorsomedial area and to a small tuberal subfornical hypothalamic area. In addition, the medial half of the PB area projects consistently to the posterior lateral hypothalamus. It is suggested that these pathways may be involved in aversive-defensive behavior, in autonomic and neuroendocrine aspects of pain, and in feeding and energy metabolism regulation.

Amygdala↗
PubMed1997

The contribution of peripheral bradykinin B2 receptors to carrageenan-evoked oedema and spinal c-Fos expression in rats.

Intraplantar co-injection of HOE140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a selective bradykinin B2 receptor antagonist (0.1, 1 and 10 micrograms), with carrageenan dose-dependently (r = 0.66, P < 0.01) reduced the carrageenan-evoked total number of c-Fos protein-like immunoreactive (c-Fos-LI) neurones (23 +/- 5%, 35 +/- 6% and 50 +/- 5% reduction; P < 0.01, P < 0.001 and P < 0.001, respectively). These reducing effects were dose-dependent for the number of c-Fos-LI neurones in both superficial (r = 0.70, P < 0.01) and deep (r = 0.53, P < 0.05) laminae. Intraplantar co-injection of HOE140 (0.1, 1 and 10 micrograms) with carrageenan significantly reduced the carrageenan-evoked paw (25 +/- 7%, 41 +/- 6% and 41 +/- 3% reduction; P < 0.001 for all) and ankle (46 +/- 6%, 61 +/- 5% and 61 +/- 5% reduction; P < 0.001 for all) oedema. Our results provide further evidence for the involvement of peripheral bradykinin B2 receptors in carrageenan-induced inflammatory nociceptive transmission.

Animals↗
PubMed1997

Chronic treatment with systemic morphine induced tolerance to the systemic and peripheral antinociceptive effects of morphine on both carrageenin induced mechanical hyperalgesia and spinal c-Fos expression in awake rats.

The effects of intravenous (3 mg/kg i.v.) and intraplantar (50 micrograms/50 microliters i.pl.) morphine were investigated on spinal c-Fos expression induced 2 h after intraplantar carrageenin (6 mg/150 microliters of saline) and on carrageenin (2 mg/150 microliters of saline) induced mechanical hyperalgesia, at day 4, in both naive and chronic morphine treated (80 mg/kg/day s.c. on days 1, 2 and 3) rats. In naive rats, i.v. and i.pl. morphine significantly decreased spinal c-Fos expression (64 +/- 4% and 44 +/- 4% reduction of control carrageenin c-Fos expression, P < 0.0001 for both, respectively) and mechanical hyperalgesia (maximal increase: 326 +/- 29%, P < 0.0001 and 87 +/- 5%, P < 0.005 of control carrageenin paw pressure vocalisation threshold (VTPP), respectively), which only developed in the carrageenin injected paw. Both treatments were ineffective in chronic morphine treated rats (92 +/- 9% and 106 +/- 6% of control carrageenin c-Fos expression; 33 +/- 17% and 30 +/- 15% increase of control carrageenin VTPP, respectively). Furthermore, only i.v. morphine increased the VTPP in the contralateral paw, in naive rats (maximal increase: 90 +/- 8%, P < 0.0001 of control carrageenin VTPP), its effects being significantly less pronounced than for the inflamed paw (P < 0.0001). These studies based on spinal c-Fos expression as an indirect marker of spinal nociceptive processes and on behavioural experiments clearly revealed that chronic treatment with systemic morphine induced tolerance to both its systemic and peripheral effects.

Analgesics, Opioid↗
PubMed1997

[The complexity of physiopharmacologic aspects of pain].

Understanding pain or, more precisely, the different types of pain, is above all a question of understanding its physiological mechanisms and, in this regard, the role of basic research has without doubt been to trigger the development of new therapeutic strategies. In an approach to these problems, the main international teams involved in pain research have attempted to develop models of experimental pain in rats. Clearly, research aimed at developing these models is controlled by certain ethical considerations; however, in this context, the end must surely justify the means. The main models used (acute or chronic inflammation, rheumatoid arthritis, peripheral neuropathy) certainly do not give a comprehensive representation of all the pain syndromes encountered in clinical practice, but they do provide new data concerning the physiological, behavioural and pharmacological aspects of pain. While giving a brief description of the complexity of the pain circuit, this article also makes reference to certain pharmacological approaches to the treatment of pain. Peripheral nociceptive messages are conveyed by a mosaic of unmyelinated free fibres distributed throughout cutaneous, muscular and articular tissue, and within the visceral walls. They are then transmitted via various nerve endings (polymodal nociceptors) by small diameter A delta and C fibres, which are activated by mechanical, thermal and chemical stimuli. It is nevertheless difficult to ascertain whether these small diameter fibres are involved only in nociception (specific nociceptors) or whether pain causes an excessive activation of these receptors, which under normal conditions have a role in the reflex that regulates various functions (nonspecific nociceptors). Numerous chemical substances play a part in generating nociceptive impulses (e.g. histamine, serotonin, prostaglandins). Furthermore, the role of neuropeptides, such as calcitonin gene-related peptide and particularly substance P, has been clearly demonstrated in the activation of early neurogenic inflammation. Other substances, such as bradykinin and cytokines, are involved in prolonging the sensation of pain. Nerve growth factor also prolongs the sensation of pain by increasing the cellular excitability of nociceptors and promoting the action of the sympathetic nervous system, which has a major role in controlling pain. The very great diversity of all these interacting substances makes the pharmacological treatment of pain extremely complex. Nevertheless, new therapeutic advances are providing interesting approaches, particularly the development of specific inhibitors of cyclo-oxygenase 2 (COX 2), which is produced by the inflammatory process. Such inhibitors would preserve COX 1, which is both constitutive and physiological, and thereby provide improved tolerability compared with currently used NSAIDs, which act upon both COX pathways. A major focus of research relating to new analgesics is the development of synthetic antagonists of bradykinin, substance P and N-methyl-D-aspartate receptors. An improved understanding of anatomical and electrophysiological processes has led to the discovery of new ascending pathways that transmit nociceptive messages to the reticular formation, the hypothalamus, and the amygdala, as well as to certain areas of the cortex. As a result the notion of one single pain centre is no longer valid. This idea is further reinforced by the knowledge that, at different stages of the pain pathway, different control systems constantly modulate the transmission of nociceptive information. Consequently, at a spinal level, activation of the large diameter cutaneous fibres (A alpha et beta) blocks pain stimuli transmitted by the small diameter fibres. Knowledge of this "gate control' mechanism of the posterior horn of the spinal cord is put to practical application in treatments involving transcutaneous electrical nerve stimulation. (ABSTRACT TRUNCATED)

Afferent Pathways↗
PubMed1997

Antinociceptive effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by a cholecystokinin type B receptor antagonist, as revealed by noxiously evoked spinal c-Fos expression in rats.

The effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or with a selective cholecystokinin (CCK)B receptor antagonist (CI988) or CCK(A) receptor antagonist (devazepide), on carrageenin-induced spinal c-Fos expression were investigated. Spinal c-Fos expression was observed 90 min after intraplantar carrageenin (6 mg/150 microl saline), with Fos-like-immunoreactive neurons preferentially located in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of superficial Fos-like-immunoreactive neurons (r2 = 0.739, P < .0001), with 63 +/- 2% (P < .0001) reduction for the highest dose. These effects were completely blocked by coadministered naloxone. Coadministration of inactive doses of i.v. RB101 (5 mg/kg) and i.p. CI988 (3 mg/kg) significantly and strongly reduced the number of carrageenin-induced, superficial, Fos-like-immunoreactive neurons (55 +/- 5% reduction of control carrageenin c-Fos expression, P < .0001). This effect was blocked by coadministered naloxone. It is important to note that coadministered RB101 and devazepide did not influence spinal c-Fos expression. None of the various drug combinations influenced the carrageenin-induced peripheral edema. These results show that RB101 dose-dependently decreases carrageenin-evoked spinal c-Fos expression. In addition, the effectiveness of RB101 can be revealed by preadministration of the CCK(B) receptor antagonist CI988. Considering the weak opioid side effects obtained with RB101 treatment and the strong increase of its effects by the CCK(B) receptor antagonist, this type of drug combination could have promising therapeutic application in the management of pain in humans.

Analgesics↗
PubMed1996

The effects of morphine on carrageenin-induced spinal c-Fos expression are completely blocked by beta-funaltrexamine, a selective mu-opioid receptor antagonist.

We have demonstrated that pre-administered morphine (3 mg/kg, i.v.) decreased spinal c-Fos expression induced 2 h after intraplantar carrageenin (55 +/- 5% reduction, P < 0.0001). These effects were completely blocked by pre-administered beta-funaltrexamine (10 mg/kg, i.v., 24 h prior to stimulation) a selective long-lasting mu-opioid receptor antagonist. In conclusion, these results clearly demonstrate that the effects of morphine on noxiously-evoked spinal c-Fos expression are essentially mediated via mu-opioid receptors.

Animals↗
PubMed1996

Interactions between NMDA- and prostaglandin receptor-mediated events in a model of inflammatory nociception.

Preadministered niflumic acid, a nonsteroidal anti-inflammatory drug (1, 3 and 9 mg/kg i.v.), dose-relatedly reduced carrageenan-evoked spinal c-Fos expression and the peripheral ankle oedema, with the highest dose reducing in parallel both parameters (55 +/- 3% reduction of carrageenan c-Fos expression, 57 +/- 13% reduction of carrageenan-evoked ankle oedema, respectively, P < 0.001 for both). Co-administration of low doses of niflumic acid and (+)-HA966, a low-efficacy partial agonist at the glycine site of the NMDA receptor (1 mg/kg i.v. + 2.5 mg/kg s.c., respectively) significantly reduced spinal c-Fos expression, this effect was significantly different from the lack of effect of niflumic acid alone or (+)-HA966 alone on spinal c-Fos expression (P < 0.01 for both drugs). Co-administered niflumic acid and (+)-HA966 did not influence the peripheral carrageenan-evoked oedema. Spinal interactions between prostaglandin-and NMDA receptor-mediated events during inflammatory nociceptive transmission are discussed.

Animals↗
PubMed1996

Selective cyclooxygenase-2 inhibition reduces carrageenan oedema and associated spinal c-Fos expression in the rat.

Pre-administered NS-398 (0.1, 1 and 10 mg/kg p.o.), a selective cyclooxygenase-2 inhibitor without gastro-intestinal side-effects, dose-dependently reduced carrageenan evoked spinal c-Fos expression (16 +/- 4%, 32 +/- 3% and 56 +/- 5% reduction, respectively) at 3 h after intraplantar carrageenan. The effects of NS-398 on carrageenan induced peripheral oedema and spinal c-Fos expression were correlated, thus demonstrating the beneficial relief of inflammatory pain.

Animals↗
PubMed1996

Ultrasonic vocalization (22-28 kHz) in a model of chronic pain, the arthritic rat: effects of analgesic drugs.

Adjuvant-induced arthritis in rats is considered as a chronic pain model. In a search for a relevant behavioural marker of the chronic pain state, we studied social interactions between an arthritic rat and a healthy partner in a neutral cage. During the test, arthritic rats emitted ultrasonic 22-28 kHz vocalizations (USV), whereas control rats did not, and showed less exploration and more immobility, but did not differ from controls in terms of social behaviours (social investigation, allogrooming). Aspirin (200 mg kg < > (en)1) or morphine (3 mg kg < > (en)1) injected intraperitoneally before the test significantly decreased USV without affecting the animals' behaviour. These results suggest that USV could be associated with affect related to aversive or painful stimuli and may constitute a behavioural marker of chronic pain in arthritic rats.

Analgesics↗
PubMed1996

Ketoprofen produces profound inhibition of spinal c-Fos protein expression resulting from an inflammatory stimulus but not from noxious heat.

This study assesses the anti-inflammatory/analgesic effects of ketoprofen a non-steroidal anti-inflammatory drug, using the method of c-Fos immunoreactivity at the spinal cord level in two models of noxious stimulation: carrageenan-induced inflammatory pain or acute noxious heat. Ketoprofen was pre-administered intravenously or orally 25 min before an intraplantar injection of carrageenan (6 mg in 150 microliters of saline) in hindpaw of the non-anaesthetised rat or before a single noxious heat (52 degrees C, 15 sec) stimulation of hindpaw of the anaesthetised rat. Three hours after carrageenan or 2 h after noxious heat, the number of spinal c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4-L5 segments and both the ankle and paw diameter, the indicator of peripheral oedema, were assessed. Pre-administered ketoprofen (1, 3 and 10 mg/kg i.v.) dose-dependently blocks the development of the carrageenan-induced spinal c-Fos protein expression and peripheral oedema, with the highest dose influencing in parallel both parameters (75 +/- 2% diminution of total number of c-Fos-LI neurons per L4-L5 section; 64 +/- 4% and 82 +/- 6% diminution of paw and ankle oedema, respectively). The effect of ketoprofen was significantly greater on the number of c-Fos-LI neurons in deep, as compared to superficial, laminae. Furthermore, the dose-dependent effects of ketoprofen on the carrageenan-induced spinal c-Fos protein expression and both the paw and ankle oedema were correlated. Oral pre-administration of ketoprofen (20 mg/kg) produced the blockage of development of the carrageenan-induced spinal c-Fos protein expression (65 +/- 3% diminution of total number of c-Fos-LI neurons per L4-L5 section) and peripheral oedema (20 +/- 3% and 59 +/- 10% diminution of paw and ankle oedema, respectively). In contrast, the same doses of both the intravenous and oral pre-administration of ketoprofen did not influence either the spinal c-Fos protein expression nor slightly enhanced paw diameter induced by a single noxious heat stimulation. This study suggests a predominant peripheral site, without excluding a central site of action of ketoprofen in the carrageenan-induced inflammation. The method of c-Fos protein-like immunoreactivity revealed ketoprofen to be more potent in comparison to members of other families of non-steroidal anti-inflammatory drugs, previously studied in the same experimental conditions of carrageenan-induced inflammatory pain.

Animals↗
PubMed1996

The contribution of GABAB receptor-mediated events to inflammatory pain processing: carrageenan oedema and associated spinal c-Fos expression in the rat.

In this pharmacological study we have assessed the effect of baclofen, a selective GABAB receptor agonist, on spinal expression of the immediate early gene c-Fos and the peripheral oedema evoked by a prolonged peripheral inflammation due to intraplantar carrageenan. Baclofen was administered intravenously 30 min before intraplantar injection of carrageenan in freely moving rats. Three hours after carrageenan the number of spinal c-Fos protein-like immunoreactive neurons and peripheral (ankle and paw) oedema were assessed. For the two series of experiments the total number of control carrageenan-evoked c-Fos protein-like immunoreactive neurons in segments L4-L5 of the spinal cord was 176 +/- 6 and 177 +/- 9 c-Fos protein-like immunoreactive neurons per section, for carrageenan control with intravenous and intraplantar saline, respectively. c-Fos protein-like immunoreactive neurons were predominantly located in laminae I-II and V-VI of the dorsal horn of the spinal cord in carrageenan controls receiving intravenous (68 +/- 3 and 69 +/- 2 c-Fos protein-like immunoreactive neurons, respectively) and intraplantar (62 +/- 4 and 71 +/- 5 c-Fos protein-like immunoreactive neurons, respectively) saline. Pre-administered systemic baclofen (0.05, 1.5 and 3 mg/kg i.v.) dose dependently reduced the total number of c-Fos protein-like immunoreactive neurons (81 +/- 3, 66 +/- 4 and 49 +/- 4% of control total number of c-Fos protein-like immunoreactive neurons, respectively), with strongest effects on the number of deep (74 +/- 3, 60 +/- 3 and 43 +/- 4% of control, respectively) as compared with superficial (90 +/- 4, 77 +/- 5 and 59 +/- 5% of control, respectively) c-Fos protein-like immunoreactive neurons. The effects of systemic baclofen on the carrageenan-induced spinal c-Fos expression and both the paw and ankle oedema were positively correlated (r = 0.479, P < 0.05 and r = 0.733, P < 0.001, respectively). Intraplantar baclofen (50 and 100 micrograms in 50 microliters of saline), simultaneously injected with intraplantar carrageenan, did not significantly influence carrageenan-evoked spinal c-Fos expression or ankle oedema. Despite the fact that the highest dose of intraplantar baclofen significantly reduced paw oedema (23 +/- 3% reduction of control paw oedema), our results are clearly in favour of a spinal site of action of systemic baclofen.

Animals↗
PubMed1996

Effects of local anaesthetics on carrageenan-evoked inflammatory nociceptive processing in the rat.

We have assessed the effects of intraplantar local anaesthetics (bupivacaine and lignocaine) on carrageenan-induced oedema, mechanical allodynia and spinal c-fos protein expression. Mechanical allodynia was evaluated using the vocalization threshold to paw pressure (VTPP) every 30 min until 60, 180 or 240 min after administration of carrageenan. Peripheral oedema, mechanical allodynia and spinal c-fos protein expression were maximal 180 min after carrageenan. Lignocaine did not influence either oedema or VTPP, but reduced spinal c-fos expression at 60 min after carrageenan without later effects. Bupivacaine induced an increase in VTPP at 30 and 60 min, limitation of oedema at 60 min and a reduction in spinal c-fos expression at 60 and 180 min, but these effects were not present 240 min after carrageenan. Intraplantar infiltration with lignocaine and bupivacaine before carrageenan transiently limited signs of inflammatory pain but did not prevent them.

Anesthetics, Local↗
PubMed1996

Concomitant administration of morphine and an N-methyl-D-aspartate receptor antagonist profoundly reduces inflammatory evoked spinal c-Fos expression.

BACKGROUND: After intraplantar injection of carrageenin, peripheral inflammation and spinal c-Fos expression are extensive, with the latter being sensitive to both large doses of morphine or N-methyl-D-aspartate receptor antagonism. The authors investigated the effects of coadministered morphine and (+)-HA966, a functional antagonist at the glycine site of the N-methyl-D-aspartate receptor, on the two parameters. METHODS: The effects of morphine, (+)-HA966 and coadministration of morphine and (+)-HA966 on spinal c-Fos expression in segments L4-L5 of the spinal cord and peripheral edema, induced at 1.5 h and 3 h after intraplantar carrageenin (6 mg/150 microliters) were studied. RESULTS: Previous coadministration of 0.3 mg/kg systemic morphine and 2.5 mg/kg subcutaneous (+)-HA966 significantly reduced c-Fos expression induced 1.5 h, but not 3 h, after carrageenin administration. However, coadministration of a larger dose of morphine (3 mg/kg) with (+)-HA966 (2.5 mg/kg) reduced c-Fos expression at 3 h after carrageenin administration, in a partially naloxone-reversible manner. CONCLUSIONS: Concurrent mu-opioid receptor activation and N-methyl-D-aspartate receptor antagonism reduces nociceptive transmission at the level of the spinal cord, as shown by the reduction of carrageenin-evoked c-Fos expression.

Analgesics, Opioid↗