Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations.

We propose a non-local model of DNA replication that takes into account the observed uncertainty on the position and time of replication initiation in eukaryote cell populations. By picturing replication initiation as a two-state system and considering all possible transition configurations, and by taking into account the chromatin's fractal dimension, we derive an analytical expression for the rate of replication initiation. This model predicts with no free parameter the temporal profiles of initiation rate, replication fork density and fraction of replicated DNA, in quantitative agreement with corresponding experimental data from both S. cerevisiae and human cells and provides a quantitative estimate of initiation site redundancy. This study shows that, to a large extent, the program that regulates the dynamics of eukaryotic DNA replication is a collective phenomenon that emerges from the stochastic nature of replication origins initiation.

The 'tonic' pain-related behaviour seen in mononeuropathic rats is modulated by morphine and naloxone.

This study investigated the sensitivity to pharmacological manipulations of a rating method, adapted from the formalin test, to measure the tonic component of the pain-related behaviour induced by creating a peripheral mononeuropathy with 4 loose ligatures around the common sciatic nerve. Although the adequacy of opioid substances in alleviating neuropathic pain is highly controversial, the effects of morphine (1 mg/kg i.v.) and naloxone (1 mg/and 3 micrograms/kg i.v.) were tested 1-2 weeks after the nerve ligatures were established, when pain-related behaviours were well developed. Morphine (1 mg/kg i.v.) induced a potent and prolonged decrease in the pain-rating score at week 2 after surgery. Either at week 1 or week 2, naloxone elicited a bidirectional dose-dependent action: a further increase in the pain-rating score with the high dose (1 mg/kg i.v.), and a paradoxical decrease in the score with the low dose of 3 micrograms/kg i.v. These effects are comparable to those already described in several rat models of inflammatory pain and, in the same model of neuropathy, using a phasic nociceptive test, the measure of the vocalization to paw pressure. A few differences in the effects of naloxone on tonic and phasic pain are noted and discussed.

Differential effects of various doses of morphine and naloxone on two nociceptive test thresholds in arthritic and normal rats.

In an attempt to clearly gauge the influence of the test used on opioid effects, the present study systemically compares the effects of various doses of morphine and naloxone with 2 differentially integrated tests: a suprasegmentally integrated test, the vocalization threshold to paw pressure and a spinally coordinated reflex, the paw withdrawal to pressure. In both normal and arthritic rats, clear differential effects of the drugs were observed: low doses of morphine (0.3 and 1 mg/kg i.v.) produced marked effects on the vocalization test, especially in arthritic rats, while it was less effective on the paw withdrawal test. Naloxone and morphine at extremely low doses (3-10 micrograms/kg, and 6 micrograms/kg i.v. respectively) clearly produced marked effects on the vocalization test, but failed to modify the paw withdrawal threshold in arthritic rats. By contrast, a high dose of naloxone (1 mg/kg i.v.) induced a comparable decrease in thresholds in both tests. This comparative study clearly shows the interest of using the vocalization threshold to paw pressure as a nociceptive test for evaluation of the antinociceptive effect of opioids. In addition, it provides useful information for a better understanding of the complex effects of morphine and the opioid antagonist naloxone in arthritic rats.

Local and remote modifications of nociceptive sensitivity during carrageenin-induced inflammation in the rat.

The modifications of the threshold for vocalization induced by pressure on the paws (both hind paws and both forepaws) were monitored at different times (15 min-96 h) following intraplantar injection of the polysaccharide carrageenin in the rat. During the first 2 h following the carrageenin injection, a decrease in vocalization threshold was observed not only for the right, injected hind paw, but also, in some rats, on paws distant from the inflamed plantar region, especially the right forepaw. This hyperalgesic effect was suppressed by locally administered Xylocaine into the right hind paw. During the 4 days following the injection, the number of rats hyperalgesic in the injected paw progressively declined. Twenty-four hours after the carrageenin injection, only a few rats still presented a clear hyperalgesia in the non-injected paws.

Antinociceptive effects of acute and 'chronic' injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats.

The tricyclic antidepressant drugs (TCAs) are commonly used in the treatment of chronic, especially neuropathic, pain. We evaluated their possible effect on a new model of neuropathic pain-related behaviour induced by ligatures tied loosely around the common sciatic nerve. The effects of 3 TCAs with different monoaminergic spectra (clomipramine, amitriptyline and desipramine) were assessed 2 weeks after surgery, the time of the maximum hyperalgesia, on a 'phasic' test (vocalization threshold to paw pressure) and on a 'tonic' test (score of the spontaneous pain-related behaviour). TCAs were acutely (0.5 and 2 mg/kg, i.v.) and 'chronically' injected (7 injections, once every half-life of the drug: 0.75 and 1.5 mg/kg, s.c., for clomipramine and 1.5 and 3 mg/kg, s.c., for amitriptyline and desipramine). Acutely injected clomipramine and amitriptyline (0.5 mg/kg, i.v.) and desipramine (2 mg/kg, i.v.) showed an antinociceptive naloxone-reversible effect, assessed by an increase in the vocalization threshold to the paw pressure test and, for amitriptyline, by a decrease in tonic pain scores. Chronically injected TCAs induced a significant and progressive increase in the vocalization threshold with a time course parallel to that of their suspected plasma or nerve tissue levels: (i) a regular increase of scores for the first 3-4 injections, (ii) then a plateau until the last injection, and (iii) a progressive decrease with a dose-dependent duration of the effect, longer than that obtained with a corresponding acute dose. This study showed that in this new model of mononeuropathy, acutely and chronically injected TCAs induce an antinociceptive effect and suggested that their analgesic action could be related to the monoaminergic spectrum of the drug in relation to the opiate systems.

Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy.

The antinociceptive action of the systemically administered alpha 2-adrenoceptor agonist clonidine was evaluated in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve, using nociceptive tests based on mechanical (vocalization threshold to paw pressure) or thermal (struggle latency to paw immersion in a cold (10 degrees C) or hot (44 degrees C) water bath) stimuli. Experiments were performed 2-3 weeks after surgery when pain-related behavior was fully developed. We demonstrated a dissociative action depending on the test used: clonidine (30-100 micrograms/kg i.v.) had a moderate effect on the abnormal reactions to the mechanical stimulus. By contrast it dramatically increased the struggle latency to hot or cold stimuli. These latter effects were completely prevented by prior administration of the alpha 2-adrenoceptor antagonist idazoxan (0.5 mg/kg i.v.).

Pharmacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour.

Trigeminal neuralgia is an example of an extreme form of neuropathic pain and continues to be a real therapeutic challenge. Although the pathophysiology of the disorder is uncertain, vascular compression of the trigeminal root resulting in damage to primary afferent neurons is thought to play a major role in the generation of pain. In the present study, we have used a recently developed rat model of trigeminal neuropathic pain, where the neuropathy is produced by a chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION), and for the first time studied the effects of various pharmacological treatments on this purely sensory model of neuropathic pain. Rats with a CCI-ION consistently display a series of spontaneous behavioural abnormalities that may be indicative of trigeminal paraesthesias/dysesthesias. A hyper-responsiveness of the territory of the ligated infraorbital nerve to light mechanical stimulation with von Frey hairs also develops at 7-12 days after the injury. Pharmacological studies indicated that the mechanical hyper-responsiveness could be reversibly abolished by local injections of alphacaine into the close proximity of the injured nerve. The allodynia-like behaviour was resistant to i.v. morphine. Similarly, single and repeated injections (using the respective T 1/2 as an interval) of tricyclic antidepressants amitriptyline and clomipramine were devoid of effects on the mechanical allodynia-like behaviour. Carbamazepine was effective only after doses (> or =10 mg/kg s.c.) that already caused disturbances in motor co-ordination in the rotarod test. Repeated injections of baclofen (3 mg/kg s.c.) partially alleviated the mechanical allodynia-like behaviour without effects on rotarod performance. The partial anti-allodynic effect of a single injection (5 mg/kg) of baclofen, which was already accompanied by slight motor disturbances, could be antagonized by CGP35348, a selective GABA(B)-receptor antagonist. Functional deficits in the GABAergic system may play an important role in the pathogenesis of this purely sensory rat model of trigeminal neuropathic pain.

The influence of the timing of bupivacaine infiltration on the time course of inflammation induced by two carrageenin injections seven days apart.

The mechanical allodynia and edema related to a subcutaneous carrageenin injection are increased by a conditioning carrageenin injection 7 days before (Guilbaud et al., 1992). In the present study, the possibility of preventing this by bupivacaine infiltration was tested. In the first part of the experiment, the time course of a carrageenin induced inflammation of the right hind paw was assessed in animals receiving local anesthetic injection (0.2 ml of bupivacaine 0.5% solution with epinephrine) either 5 min before (BUPI PRE group) or 60 min after (BUPI POST group) the carrageenin injection (0.2 ml of 1% solution). Control groups received saline (0.2 ml) with the same timing. In the second part of the experiment, 7 days later, a carrageenin injection was performed either in the right or the left hind paw. Mechanical allodynia and edema were evaluated by the vocalization threshold to paw pressure (VTPP) and paw circumference (PC) in both hind paws at 1, 2, 4, 24 h and 7 days after both carrageenin injections. The first carrageenin injection induced mechanical allodynia and edema maximal at 240 min (42% reduction of VTPP; 23% increase in PC) and the influence of bupivacaine on the VTPP and PC was similar to previous results (Fletcher et al., 1996). The second ipsilateral carrageenin injection induced a more pronounced inflammation in the control groups and BUPI POST group than the first injection (P < 0.001). In contrast, the increase in allodynia and edema was less intense in the BUPI PRE group than in the other groups (P < 0.0001 and P < 0.02 respectively). Bupivacaine injections had no effect on allodynia and edema related to a second contra-lateral carrageenin injection. These results suggest that bupivacaine infiltration, when administered before the first conditioning injection of carrageenin, can prevent the reinforcement of mechanical allodynia and edema related to a second ipsilateral injection of carrageenin 7 days later.

Effects of intraplantar morphine on paw edema and pain-related behaviour in a rat model of repeated acute inflammation.

Recent studies suggest that peripheral morphine may represent a valuable treatment in inflammatory painful diseases. This study examined effects of intraplantar morphine against noxious pressure and paw edema in rats with repeated acute inflammation induced by two carrageenin injections 7 days apart. This model mimics at least partly some aspects of recurrent inflammatory pain encountered in the clinical situation. In the first part of the experiment, the effect of intraplantar morphine into the inflamed hindpaw was determined 3 h after carrageenin injection. Intraplantar morphine (50-200 microg) produced significant elevations of vocalization thresholds to paw pressure in inflamed but not in non-inflamed paws after both carrageenin injection; these effects were reversible by intraplantar naloxone methiodide (40 microg). The effects of intraplantar morphine (150 microg) were similar in magnitude to that of intravenous morphine (1 mg/kg) after first carrageenin injection. In contrast, at doses of 150-200 microg, they were significantly lower after second ipsilateral carrageenin injection 7 days later, than first injection. Intraplantar morphine (100-200 microg) had no effect on paw edema associated with both carrageenin injections. In the second part of the experiment, intraplantar morphine was injected 10 min before the first injection of carrageenin. Intraplantar morphine (50 microg) was ineffective, whereas morphine (100-200 microg) prevented reduction of vocalization thresholds to paw pressure of inflamed hindpaw for 3 h. The intraplantar injection of morphine (100 and 150 microg) produced a transient increase in the volume of inflamed hindpaw, not reversible by intraplantar naloxone methiodide (40 microg). Pretreatment with intraplantar morphine had no effect on reduction of vocalization thresholds to paw pressure and edema related to a second ipsilateral injection of carrageenin 7 days later. These findings suggest that peripheral morphine may be useful for the clinical management of acute inflammatory pain rather than in recurrent inflammatory painful situations.

Influence of a specific 5-HT3 antagonist on carrageenan-induced hyperalgesia in rats.

The effect of ICS 205-930 (ICS), a specific 5-HT3 antagonist, was studied on carrageenan (CAR)-induced rat paw inflammation to assess the involvement of endogenous released serotonin (5-HT) in the observed hyperalgesia. Studies were performed using a behavioural test, measuring the threshold stimulus necessary to elicit vocalization by gradually increasing pressure applied to the paw. When administered (s.c., in the CAR-injected paw) either 20 min before, simultaneously or 20 min after CAR, ICS (10(-11) mol/kg, i.e., 3.2 ng/kg) completely prevented the hyperalgesia in both the injected and non-injected hind paws. This effect was prolonged for 90 min, equivalent to the effect on CAR on 5-HT release. Moreover, ICS increased the vocalization threshold over the pre-drug values in normal and CAR-treated rats when injected both 20 min before and simultaneously with the polysaccharide. On the contrary, it did not reduce the hyperalgesia, when injected 2 h after CAR. ICS had no effect at any time of administration on paw oedema. These results suggest that the early inflammatory sensitization of peripheral nociceptors is mainly dependent on the release of serotonin and that the hyperalgesic effect of the monoamine involves 5-HT3(M) receptors which do not seem to be involved in the early development of oedema.

Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain.

This study evaluated the antinociceptive effects of systemically administered selective opioid agonists of mu (DAMGO), delta (BUBU) and kappa (U 69593) receptors on the vocalization threshold to paw pressure in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve. DAMGO (0.5-2 mg/kg), BUBU (1.5-6 mg/kg) and U 69593 (0.75-3 mg/kg) injected intravenously (i.v.) produced a potent long-lasting antinociceptive effect on both hind paws. The effects on the lesioned paw were clearly and statistically more potent than for the non-lesioned paw. The selective antinociceptive effect of 2 mg/kg DAMGO, 3 mg/kg BUBU and 1.5 mg/kg U 69593 were completely prevented by prior administration of the appropriate antagonists: 0.1 mg/kg naloxone, 1 mg/kg naltrindole and 0.4 mg/kg MR 2266. The present data clearly show that an acute i.v. injection of these selective opioid agonists induces potent antinociceptive effects in a rat model of peripheral neuropathy. These data are discussed with regard to the classical view that there is opioid resistance in neuropathic pain.

Are mechanical and cold allodynia in mononeuropathic and arthritic rats relieved by systemic treatment with calcitonin or guanethidine?

The putative antinociceptive action of guanethidine and calcitonin systemically injected has been compared in 2 rat models of persistent experimental pain: Freund's adjuvant-induced arthritis (n = 29) and mononeuropathy induced by 4 loose ligatures around the sciatic nerve (n = 24). Guanethidine (30 mg/kg, i.v.) and calcitonin (0.125 mg, s.c.) were injected once a day over 1 week, when hyperalgesia was fully developed. The antinociceptive action was gauged using nociceptive tests based on mechanical or cold stimuli (vocalization threshold to paw pressure and struggle latency to 10 degrees C, respectively), and the score of spontaneous pain-related behavior was measured on the basis of the abnormal hind paw position. No antinociceptive action was observed in calcitonin-compared to saline-injected rats, either in arthritic or neuropathic animals. Guanethidine treatment was ineffective on hyperalgesia exhibited in arthritic rats but was able to reduce reliably and even suppress the abnormal reactions to cold stimulus in neuropathic animals. The lack of hypoalgesic action of calcitonin versus its beneficial action in bone repair, as well as the possible role(s) of the sympathetic system in neuropathic versus arthritic pain and in hyperalgesia versus physical signs of inflammation, are discussed.

Neurones responding to noxious stimulation in VB complex and caudal adjacent regions in the thalamus of the rat.

(1) 163 cells responding to mechanical cutaneous stimulation have been recorded in VB complex and caudal adjacent region in rats anaesthetized with a mixture of 2/3 N2O--1/3 O2 and 0.5% halothane. (2) 51 cells were exclusively activated by non-noxious cutaneous stimuli applied to restricted and contralateral receptive fields (RF) and had the classical characteristics of "lemniscal" responses. 93 cells responded only to noxious mechanical stimuli (N cells) and had either uni- or bilateral receptive fields. 19 cells responded both to noxious and non-noxious stimuli (NnN cells). (3) When tested with intense electrical stimuli applied transcutaneously or on the sural nerve, N and NnN cells responded with a late irregular discharge. Poststimulus histograms obtained in one-third of these units revealed that the late component was consistent with a C fibre input; some of responses were consistent with A delta fibre input. NnN cells also had a short latency discharge probably due to A alpha fibre involvement. (4) When tested with other intense stimuli such as noxious radiant heat or noxious visceral stimulation induced by intraperitoneal injection of bradykinin, N and NnN cells were strongly activated. (5) The different kinds of cells were scattered in VB and PO and no significant differences were found between cells recorded in VB and caudal adjacent region (PO); however, a rostrocaudal organization of the cells, according to the location of their RF on the caudal or rostral part of the body, was clear not only for the Nn cells but also for N and NnN cells.

Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy.

A model of experimental peripheral neuropathy producing pain-related disorders has recently been described in the rat. The present study aimed to investigate, using a different and quantifiable behavioural approach, the abnormal pain-related sensations in the animals. The neuropathy was produced by 4 ligatures tied loosely around the common sciatic nerve. 6-8 days after surgery, most of the rats exhibited pain-related disorders ipsilateral to the sciatic ligation, which became maximal 2 weeks after surgery. Mechanical noxious stimulation (pinching of the hind paw) revealed hyperalgesia in all the animals. Rats also exhibited allodynia when tested with the vocalization threshold test to paw pressure (mean vocalization thresholds were 65.5 +/- 3.6% of the preoperative control, P less than 0.01, n = 95). Tests using heat (40, 42, 44, 46 degrees C) and cold (10 degrees C) stimulation (immersion of the rat's hind paw in a bath until it was observed to struggle) indicated hyperalgesia to noxious heat (decrease of 30% in the immersion duration (ID) at a temperature of 46 degrees C), and allodynia to non-noxious heat (decrease of 30% in the temperature of the struggle threshold) and to cold stimulation (decrease by 40% in the ID). In addition, the animals showed modifications in the spontaneous postures of the affected hind paw in a natural setting, suggesting a 'spontaneous' pain-related behaviour (the mean 'pain' rating, derived from the technique used for the formalin test and numbered 0-5, was 2.8 +/- 0.4, P less than 0.01, n = 12). Lastly, sensitized responses were observed to mechanical stimulation after thermal stimulation in the non-noxious range applied to the lesioned but not the non-lesioned paw. The time course of pain-related disorders was comparable whatever the behavioural test, with recovery 2 months after surgery. These results clearly show that the neuropathy produces abnormal pain-related disorders in the rat, which are reminiscent of those observed in some human neuropathies.

Differential action of morphine and various opioid agonists on thermal allodynia and hyperalgesia in mononeuropathic rats.

In a rat model of mononeuropathy produced by 4 loose ligatures around the common sciatic nerve, the effects of 1 mg/kg morphine and mu-, delta- and kappa-agonists, DAMGO (2 and 3 mg/kg), BUBUC (3 and 6 mg/kg) and U-69,593 (1.5 mg/kg), were evaluated by measuring the struggle latency (SL in sec) to immersion of the paw on the nerve-injured side in a cold (10 degrees C) or hot (42 degrees C, 44 degrees C, and 46 degrees C) water bath. Experiments were performed 2 weeks after surgery. The agonists were used at doses that produced potent antinociceptive effects on the vocalization test in this model. At 46 degrees C (clearly in the noxious range), only morphine and DAMGO had significant effects. The effect of morphine lasted for more than 2 h with a maximum at 40 min (SL = 13.8 +/- 1.6 sec, 252% of control values). For 2 and 3 mg/kg DAMGO, the dose-related effect lasted for 120 min at least, with a maximum at 20-40 min (SL = 6.0 +/- 0.5 and 8.8 +/- 0.7 sec, 148% and 170% of control values, respectively). These effects were more potent and prolonged than in normal rats and were reversed by 0.1 mg/kg naloxone i.v. By contrast, morphine and all selective agonists failed to relieve the abnormal reactions to 10 degrees C, 42 degrees C (in the non-noxious range) and 44 degrees C (at the noxious threshold) stimuli. Our data illustrate a differential effect of opioids on nociceptive tests based on different stimulus modalities and intensities in this model of mononeuropathic pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioural evidence that systemic morphine may modulate a phasic pain-related behaviour in a rat model of peripheral mononeuropathy.

In a model of peripheral mononeuropathy produced by 4 ligatures around the sciatic nerve, we investigated the effects of various i.v. doses of morphine on the vocalization thresholds elicited by paw pressure and compared the effects obtained with the same doses in normal rats. In neuropathic rats, morphine (0.1 and 0.3 mg/kg) produced a significant analgesic effect on the lesioned hind paw, maximum at 15 min post injection with a recovery at 20-25 min. For doses of 0.6 and 1 mg/kg, a modification of the kinetics was observed, with maximum effect at 20-30 min post injection and a recovery at 50-80 min. An analgesic effect was also observed on the unlesioned side, significantly less potent than that observed on the lesioned paw. The effect of 1 mg/kg morphine was almost totally reversed by a 0.1 mg/kg dose of systemic naloxone. The effects induced by the successive doses of morphine on the lesioned paw appeared higher than in normal rats (maximum vocalization thresholds (% of control) following 1 mg/kg morphine (N = 12) were 193.92 +/- 6.57% versus 154 +/- 3.5% in normal rats N = 3), whereas they were comparable to those obtained from the sham-operated paw. The present data clearly show that morphine induces potent antinociceptive effects in a rat model of neuropathy, which seems to contradict the classical view that neuropathic pain is opioid resistant. Some possible pathophysiological mechanisms are discussed.

The enhancement of morphine antinociception by a CCKB receptor antagonist in the rat depends on the phase of inflammation and the intensity of carrageenin-induced hyperalgesia.

The ability of the cholecystokinin B (CCKB) receptor antagonist L-365,260 to modulate the antinociceptive action of systemic morphine was investigated using the well established rat model of localized inflammation induced by intraplantar injection of carrageenin. The effects of morphine (0.1-1 mg/kg i.v.) alone or in combination with the CCKB receptor antagonist (0.2 mg/kg s.c.) were determined at different time-points (at 1, 3 and 24 h) after the injection of carrageenin by measuring the vocalization threshold to paw pressure. L-365,260 was found to be ineffective in modulating the responses to all doses of morphine at 1 and 24 h after carrageenin. By contrast, at 3 h, the CCKB receptor antagonist reversed the ineffectiveness of the low dose (0.1 mg/kg i.v.) of morphine on the inflamed paw. Further, in the L-365,260-pretreated rats, a significant correlation between the antinociceptive effect of the low dose (0.1 mg/kg) of morphine and the intensity of the mechanical hyperalgesia was observed, indicating that the CCK control of the degree of sensitivity to opioids can vary among-the animals. Our data illustrate a differential and limited effect of L-365,260 on opioid antinociception in carrageenin-injected rats, depending on the dose of morphine, the phase of inflammation and the intensity of hyperalgesia.

Analgesia induced by electrical stimulation of the inferior centralis nucleus of the raphe in the cat.

In the cat, electrical stimulation of the inferior central nucleus of the raphe induces a powerful analgesia. This stimulation totally suppresses the behavioural reactions elicited by strong pinches applied to the tail or to the four limbs; it strongly modifies the threshold of the jaw opening reflex obtained by tooth pulp stimulation and considerably affects the behavioural reactions elicited by continuing such stimulation. The results can be considered as evidence that the mechanism of analgesia from the inferior raphe nucleus is similar to that already described in the dorsal raphe nucleus. The analgesia obtained by stimulation of raphe nuclei seems to be sustained by serotoninergic mechanisms and relationships between these are discussed. In preliminary experiments, analgesia induced by CI stimulation has been suppressed by administration of naloxone, a specific opiate antagonist.

Low dose of morphine strongly depresses responses of specific nociceptive neurones in the ventrobasal complex of the rat.

Effects of low intravenous doses of morphine (30, 100 and 1000 micrograms/kg) upon unitary responses of 22 'nociceptive' and 5 'non-nociceptive' units recorded in the ventrobasal (VB) complex of the rat were analyzed. The responses of the 'non-noxious' neurones were not depressed by morphine. By contrast, for all these doses there was a decrease of the total number of spikes and of the maximal firing rate of the responses of the noxious neurones. The depressive effect was significantly dose-related (with linear semi-logarithmic dose-response curve) and naloxone-reversible. Similar effects were observed upon responses to pinches and noxious heat. The ED50 which was close to 90 micrograms/kg for these thalamic responses to pinches is much more lower than that evaluated for spinal dorsal horn responses under the same anaesthetic conditions. Therefore the depressive effect of low doses observed for VB neurones seems to be mainly of supraspinal origin.

Aspirin clearly depresses responses of ventrobasal thalamus neurons to joint stimuli in arthritic rats.

This study dealt with the effect of aspirin upon activities of 17 ventrobasal thalamic neurons recorded in 17 rats rendered arthritic by injection of Freund's adjuvant into the tail. These neurons presented reproducible responses to mobilization and/or mild lateral pressure on a joint and were recorded for at least 40 min after aspirin administration. After intravenous injection of aspirin at the dose of 50 mg/kg (13 neurons tested), there was a progressive decrease in the number of spikes in the discharges. The maximum effect occurred at 30 min where the mean value of the response expressed as a percentage of the control was m = 34.62 +/- 7.5% (n = 13, p less than or equal to 0.001). Recovery was progressive and could be considered as complete at 60 min. By contrast, no significant modification of the spontaneous firing has been observed. With lower doses of aspirin (12.5 or 25 mg/kg tested with 4 neurons) there was respectively no clear depressive effect or only a transient decrease of the response.