Spinal dopaminergic D1-and D2-like receptors have a sex-dependent effect in an experimental model of fibromyalgia.

There is evidence about the importance of sex in pain. The purpose of this study was to investigate the effect of sex in the antiallodynic activity of spinal dopamine D1-and D2-like receptors in a model of fibromyalgia-type pain in rats. Reserpine induced the same extent of tactile allodynia in female and male rats. Intrathecal injection of SCH-23390 (3-30 nmol, D1-like receptor antagonist), pramipexole (0.15-15 nmol) or quinpirole (1-10 nmol D2-like receptor agonists) increased withdrawal threshold in reserpine-treated female rats. Those drugs induced a greater antiallodynic effect in female rats. Sex-difference was also observed in a nerve injury model. Ovariectomy abated the antiallodynic effect of SCH-23390 (30 nmol) in reserpine-treated rats, while systemic reconstitution of 17ß-estradiol levels or intrathecal injection of estrogen receptor-α agonist protopanaxatriol in ovariectomized reserpine-treated females restored the antiallodynic effect of SCH-23390. Intrathecal administration of ICI-182,780 (estrogen receptor-α/ß antagonist) or methyl-piperidino-pyrazole hydrate (estrogen receptor-α antagonist) abated 17ß-estradiol-restored antiallodynic effect of SCH-23390 in rats. In contrast, ovariectomy slightly reduced the effect of pramipexole (15 nmol) or quinpirole (10 nmol) in reserpine-treated rats, whereas systemic reconstitution of 17ß-estradiol levels did not modify the antiallodynic effect of both drugs. Combination 17ß-estradiol/progesterone, but not 17ß-estradiol nor progesterone alone, restored the antiallodynic effect of pramipexole and quinpirole in the rats. Mifepristone (progesterone receptor antagonist) abated 17ß-estradiol + progesterone restoration of the antiallodynic effect of pramipexole and quinpirole. These data suggest that the antiallodynic effect of dopamine D1-and D2-like receptors in fibromyalgia-type pain depends on spinal 17ß-estradiol/estrogen receptor-α and progesterone receptors, respectively.

Neurophysiopathological Aspects of Paclitaxel-induced Peripheral Neuropathy.

Chemotherapy is widely used as a primary treatment or adjuvant therapy for cancer. Anti-microtubule agents (such as paclitaxel and docetaxel) are used for treating many types of cancer, either alone or in combination. However, their use has negative consequences that restrict the treatment's ability to continue. The principal negative effect is the so-called chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a complex ailment that depends on diversity in the mechanisms of action of the different chemotherapy drugs, which are not fully understood. In this paper, we review several neurophysiological and pathological characteristics, such as morphological changes, changes in ion channels, mitochondria and oxidative stress, cell death, changes in the immune response, and synaptic control, as well as the characteristics of neuropathic pain produced by paclitaxel.

The nucleus accumbens dopamine increase, typically triggered by sexual stimuli in male rats, is no longer produced when animals are sexually inhibited due to sexual satiety.

RATIONALE: Exposure of male rats to an inaccessible receptive female and copulation increases dopamine (DA) levels in the nucleus accumbens (NAcc). Males copulating to satiety become sexually inhibited and most of them do not display sexual activity when presented with a sexually receptive female 24 h later. This inhibitory state can be pharmacologically reversed. There are no studies exploring NAcc DA levels during this sexual inhibitory state. OBJECTIVES: To characterize changes in NAcc DA and its metabolites' levels during sexual satiety development, during the well-established sexual inhibitory state 24 h later, and during its pharmacological reversal. METHODS: Changes in NAcc DA and its metabolites were measured in sexually experienced male rats, using in vivo microdialysis, during copulation to satiety, when presented to a new sexually receptive female 24 h later, and during the pharmacological reversal of the sexual inhibition by anandamide. RESULTS: NAcc DA levels remained increased during copulation to satiety. DA basal levels were significantly reduced 24 h after copulation to satiety, as compared to the initial basal levels. Presenting a receptive female behind a barrier 24 h after satiety did not induce the typical NAcc DA elevation in the sexually satiated males but there was a decrease that persisted when they got access to the female, with which they did not copulate. Anandamide injection slightly increased NAcc DA levels coinciding with sexual satiety reversal. CONCLUSIONS: Reduced NAcc DA concentrations coincide with the inhibition of an instinctive, natural rewarding behavior suggesting that there might be a DA concentration threshold needed to be responsive to a rewarding stimulus.

Expression of the dopaminergic D1 and D2 receptors in the anterior cingulate cortex in a model of neuropathic pain.

BACKGROUND: The anterior cingulate cortex (ACC) has been related to the affective component of pain. Dopaminergic mesocortical circuits, including the ACC, are able to inhibit neuropathic nociception measured as autotomy behaviour. We determined the changes in dopamine D1 and D2 (D1R and D2R) receptor expression in the ACC (cg1 and cg2) in an animal model of neuropathic pain. The neuropathic group had noxious heat applied in the right hind paw followed 30 min. later by right sciatic denervation. Autotomy score (AS) was recorded for eight days and subsequently classified in low, medium and high AS groups. The control consisted of naïve animals.A semiquantitative RT-PCR procedure was done to determine mRNA levels for D1R and D2R in cg1 and cg2, and protein levels were measured by Western Blot. RESULTS: The results of D1R mRNA in cg1 showed a decrease in all groups. D2R mRNA levels in cg1 decreased in low AS and increased in medium and high AS. Regarding D1R in cg2, there was an increase in all groups. D2R expression levels in cg2 decreased in all groups. In cg1, the D2R mRNA correlated positively with autotomy behaviour. Protein levels of D2R in cg1 increased in all groups but to a higher degree in low AS. In cg2 D2R protein only decreased discretely. D1R protein was not found in either ACC region. CONCLUSIONS: This is the first evidence of an increase of inhibitory dopaminergic receptor (D2R) mRNA and protein in cg1 in correlation with nociceptive behaviour in a neuropathic model of pain in the rat.

Inflammatory nociception diminishes dopamine release and increases dopamine D2 receptor mRNA in the rat's insular cortex.

BACKGROUND: The insular cortex (IC) receives somatosensory afferent input and has been related to nociceptive input. It has dopaminergic terminals and D1 (D1R) -excitatory- and D2 (D2R) -inhibitory- receptors. D2R activation with a selective agonist, as well as D1R blockade with antagonists in the IC, diminish neuropathic nociception in a nerve transection model. An intraplantar injection of carrageenan and acute thermonociception (plantar test) were performed to measure the response to inflammation (paw withdrawal latency, PWL). Simultaneously, a freely moving microdyalisis technique and HPLC were used to measure the release of dopamine and its metabolites in the IC. Plantar test was applied prior, one and three hours after inflammation. Also, mRNA levels of D1 and D2R's were measured in the IC after three hours of inflammation. RESULTS: The results showed a gradual decrease in the release of dopamine, Dopac and HVA after inflammation. The decrease correlates with a decrease in PWL. D2R's increased their mRNA expression compared to the controls. In regard of D1R's, there was a decrease in their mRNA levels compared to the controls. CONCLUSIONS: Our results showed that the decreased extracellular levels of dopamine induced by inflammation correlated with the level of pain-related behaviour. These results also showed the increase in dopaminergic mediated inhibition by an increase in D2R's and a decrease in D1R's mRNA. There is a possible differential mechanism regarding the regulation of excitatory and inhibitory dopaminergic receptors triggered by inflammation.

Dehydroepiandrosterone increases tonic and phasic dopamine release in the striatum.

Dehydroepiandrosterone (DHEA) modulates dopaminergic neurotransmission. It takes part in neurologic and psychiatric diseases involving monoamine neurotransmitters. Earlier results show that DHEA (120-min treatment) reduced striatal dopamine (DA) turnover in rats, suggesting a reduced DA release. Some investigations report that DHEA increases DA release but inhibits motor activity, which seems contradictory. This research examines the effect of DHEA on striatal DA release, its metabolism and motor activity. Male Wistar rats were implanted in the striatum with a cannula for in vivo microdialysis. DHEA was administered (120 mg/kg) and dialysates were collected for 280 min. A depolarizing stimulus was applied at 120 min. Samples were analyzed by HPLC-ED to determine the concentration of DA and its metabolites. The effect of DHEA on motor activity was also evaluated during 120 min. Extracellular DA concentration was greater in treated animals both before and after depolarization. In contrast, DHEA reduced the areas below the curves for DA metabolites and DA/metabolite ratios. DHEA also reduced motor activity, remarkably in the first 20 min after treatment. In summary, DHEA yielded a stimulatory effect on striatal DA release that was not reflected in neither DA metabolism nor motor activity. Thus, DHEA resembles the effect of typical antipsychotics, increasing DA release but reducing behavioral activation.

Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action.

Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.

Cellular Mechanism for Specific Mechanical Antinociception by D2-like Receptor at the Spinal Cord Level.

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.

Chemotherapy-induced neuropathic pain characteristics in Mexico's National Cancer Center pain clinic.

Introduction: Chemotherapy (CT) is one of the most commonly used pharmacological approaches in cancer treatment. However, CT induces damage to several tissues causing significant deleterious effects in cancer survivors being chemotherapy-induced neuropathic pain (CINP) among the most commonly reported. CINP is thought to be present in up to 68.1% of the patients within 1 month of receiving CT. Due to the fact that reliable statistic information is scarce in several Latin American countries' diagnosis and treatment of this side-effect may be delayed directly affecting patients. Therefore, the aim of the present study was to determine and present the incidence and features of CINP in patients with cancer attending the Pain Management Clinic at Mexicos' National Institute of Cancerology in Mexico City. Methods: We performed a retrospective, file-based analysis of all the patients treated in the Pain Management Clinic at the National Institute at Cancer in Mexico from January 2016 to January 2017. Results: CINP was found in 30.9% of the patients. The basal VAS was on average 2.5 upon arrival to the Pain Management Unit and 2.4 at the end of treatment (p>0.05). The patients with the highest risk of developing CINP were those treated with paclitaxel Odds ratio 8.3 (p<0.01), followed by platins OR 4 (p<0.01), vincristine OR 1.5 (p=0.01) and thalidomide OR 1.1 (p=0.01). Conclusion: Incidence of CINP was similar to previous reports; however, the number of variables related to this type of pain in our cohort may open a new line of research and highlight the importance of this particular issue to our health system. It is necessary to develop a mechanism to predict the risk of patients to suffer CINP and to search the mechanism to control and reduce the suffering related to the current treatments.

Ceftriaxone and clavulanic acid induce antiallodynia and anti-inflammatory effects in rats using the carrageenan model.

INTRODUCTION: Ceftriaxone (CFX) and clavulanic acid (CA) are 2 ß-lactam molecules widely used as antibiotics. However, several reports of their antiallodynic properties have been published in recent years. Although this effect has been considered mostly due to a GLT1 overexpression, these molecules have also been proven to induce direct immunomodulation. In this work, we determine the acute analgesic effect of CFX and CA in an inflammatory pain model and assess if their administration may induce anti-inflammatory effects. METHODS: The carrageenan (Carr) test was used as an inflammatory pain model. Both mechanical and thermal responses were analyzed after CFX and CA administration at different times. A plethysmometer was used to determine inflammation. Also, TNF-α and IL-10 serum concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: Both CFX and CA induced a significant thermal antiallodynic effect 3 and 24 h after administration. Furthermore, CA induced a mechanical antiallodynic effect 30, 60, and 90 min after administration. Moreover, a significant anti-inflammatory effect was found for both molecules 24 h after Carr injection. Also, both CA and CFX modulated TNF-α and IL-10 serum concentrations at different times. CONCLUSION: Our results provide evidence that both CFX and CA cause an analgesic effect on a Carr inflammatory pain model and that said analgesic effect differs between each ß-lactam molecule. Furthermore, this effect may be related to an anti-inflammatory effect of both molecules and a direct TNF-α and IL-10 serum concentration modulation.

Taurine in the anterior cingulate cortex diminishes neuropathic nociception: a possible interaction with the glycine(A) receptor.

Taurine is an inhibitory amino-acid which has been proposed as a nociceptive process neuromodulator. The glycine(A) receptor (glyR(A)) has been postulated as a receptor in which taurine exerts its function. Functional image studies have documented the role of the anterior cingulate cortex (ACC) in the affective component of pain. The aim of this study was to investigate the role of taurine as a glycinergic agonist in the ACC using a neuropathic pain model related to autotomy behaviour (AB). In order to test whether glyR(A) is responsible for taurine actions, we microinjected strychnine, a glyR(A) antagonist. We used taurine microinjected into the ACC, followed by a thermonociceptive stimulus and a sciatic denervation. Chronic nociception was measured by the autotomy score, onset and incidence. The administration of taurine 7 days after denervation modifies the temporal course of AB by inhibiting it. Our results showed a decreased autotomy score and incidence in the taurine groups, as well as a delay in the onset. Those experimental groups in which strychnine was microinjected into the ACC, either on its own or before the microinjection of taurine, showed no difference as compared to the control group. When taurine was microinjected prior to strychnine, the group behaved as if only taurine had been administered. Our results evidence a significant neuropathic nociception relief measured as an AB decrease by the microinjection of taurine into the ACC. Besides, the role of the glyR(A) is evidenced by the fact that strychnine antagonises the antinociceptive effect of taurine.

Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. AIM OF THE STUDY: Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. MATERIAL AND METHODS: Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. RESULTS: Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. CONCLUSION: The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.

A D2-like receptor family agonist produces analgesia in mechanonociception but not in thermonociception at the spinal cord level in rats.

The administration of dopaminergic drugs produces analgesia in individuals experiencing different types of pain. Analgesia induced by these drugs at the spinal cord level is mediated by D2-like agonists, which specifically inhibit the detection of nociceptive stimuli by sensory afferents. The extent of the analgesia provided by spinal dopamine agonists remains controversial, and the cellular mechanism of this analgesic process is poorly understood. The objective of this study was to evaluate the analgesic effect of quinpirole, a D2-like agonist, based on two nociceptive tests and at various doses that were selected to specifically activate dopamine receptors. We found that intrathecal quinpirole administration produces analgesia of mechanical but not thermal nociception and that the analgesic effect of quinpirole is reversed by a mix of D2, D3, and D4 receptor-specific antagonists, suggesting that the activation of all D2-like receptors is involved in the analgesia produced by intrathecal quinpirole. The differential effect on thermal and mechanical nociception was also tested upon the activation of µ-opioid receptors. As reported previously, low doses of the µ-opioid receptor agonist DAMGO produced analgesia of only thermonociception. This evidence shows that a D2-like receptor agonist administered at the spinal cord level produces analgesia specific to mechanonociception but not thermonociception.

Inhibition of peripheral nociceptors by aminoglycosides produces analgesia in inflammatory pain models in the rat.

Aminoglycosides (AGs) modulate nociceptors and ionic channels expressed in sensory neurons. The AG applied in situ could be useful to alleviate hyperalgesia in animal models of inflammatory pain. We tested streptomycin (ST) and neomycin (NEO) as analgesic agents applied in situ in rat paw inflammation caused by formalin or carrageenan administration. The action of ST and NEO on the action potential discharge produced by acidic stimuli in isolated dorsal root ganglion neurons was also studied in current-clamp recordings. In the formalin test, ST and NEO significantly reduced the nociceptive behaviour. ST reduced the N-(4-methyl-2-quinazolinyl)-guanidine (GMQ)-induced nociceptive behaviour, and NEO diminished the hyperalgesia to thermonociception and mechanonociception produced by CAR. In the current-clamp experiments, ST and NEO reduced the generation of action potentials when an acidic solution was applied. We conclude that ST and NEO produce analgesia to inflammatory pain, an effect that is due in part to the inhibition of ASIC activation in sensory neurons.

Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex.

The anterior cingulate cortex (ACC) plays a key role in pain processing. It has been reported that increased activity of glutamatergic projections into the ACC intensifies nociception; whereas dopaminergic projections inhibit it. The aim of this study was to evaluate the role of dopaminergic and NMDA systems of the ACC in the modulation of long-term nociception elicited by sciatic denervation in the rat. Score, onset and incidence of long-term nociception were measured by the autotomy behavior. The effects of a single microinjection into the ACC of different doses of dopamine (100 nM, 100 microM and 100 mM), a NMDA receptor antagonist (MK801 200 nM and 9.34 mM) and amantadine, a dopamine agonist and NMDA receptor antagonist (10, 100 and 1000 microM) were tested on long-term nociception. Dopamine diminished autotomy behavior in an inverse dose-dependent manner, with dopamine 100 nM as most effective concentration. MK801 and amantadine elicited a significant reduction on autotomy score. Prior injections of D1 and D2 receptor antagonists blocked the antinociceptive effects of amantadine on long-term nociceptive behavior. The present study suggests an interaction between dopaminergic and glutamatergic systems within the ACC in the genesis and maintenance of long-term nociception.

Scopolamine into the anterior cingulate cortex diminishes nociception in a neuropathic pain model in the rat: an interruption of 'nociception-related memory acquisition'?

The cingulate cortex plays a key role in the affective component related to pain perception. This structure receives cholinergic projections and also plays a role in memory processing. Therefore, we propose that the cholinergic system in the anterior cingulate cortex is involved in the nociceptive memory process. We used scopolamine (10 microg in 0.25 mircrol/saline) microinjected into the anterior cingulate cortex, either before thermonociception followed by a sciatic denervation, between thermonociception and denervation or after both procedures (n=10 each). The vehicle group (saline solution 0.9%, n=14) was microinjected before thermonociception. Chronic nociception was measured by the autotomy score, which onset and incidence were also determined. Group scopolamine-thermonociception-denervation (STD) presented the lowest autotomy score as compared to vehicle and group thermonociception-denervation-scopolamine (TDS) (vehicle vs. STD, p=0.002, STD vs. TDS, p=0.001). Group thermonociception-scopolamine-denervation (TSD) showed a diminished autotomy score when compared to TDS (p=0.053). STD group showed a delay in the onset of AB as compared to the rest of the groups. Group TSD presented a significative delay (p=0.048) in AB onset when compared to group TDS. There were no differences in the incidence between groups. The results show that nociception-related memory processed in the anterior cingulate cortex is susceptible of being modified by the cholinergic transmission blockade. When scopolamine is microinjected prior to the nociceptive stimuli, nociception-related memory acquisition is prevented. The evidence obtained in this study shows the role of the anterior cingulate cortex in the acquisition of nociception-related memory.

Self-injury behaviour induced by intraplantar carrageenan infiltration: a model of tonic nociception.

The research of chronic nociception using whole animals is an approach plagued with methodological drawbacks within the ethical realm, as well as difficulties in the analysis and interpretation of time dependent results. On this work, we propose an experimental model that displays tonic nociception measured as a quantifiable self-injury behaviour (SIB) produced by the inflammation of soft tissue located in the paw of the rat elicited by carrageenan 1% (CAR) infiltration. We established five categories or levels for the analysis of the self-injury behaviour reflecting the intensity of rat nociception triggered by CAR infiltration. In addition, we determine that this model does not induce inescapable pain by noticing no significant differences when measuring weight gain and sexual behaviour. We propose this nociception model as physiologically and ethically appropriate for the study of long-lasting nociception.

Inflammatory nociception responses do not vary with age, but diminish with the pain history.

Some of the relevant factors that must be considered when dealing with old age include its growing numbers in the general population and pain contention in this age group. In this sense, it is important to study whether antinociceptive responses change with age. To elucidate this point, persistent pain in animals is the preferred model. In addition, the response to inflammatory pain in the same individual must be explored along its lifetime. Male Wistar rats were infiltrated with carrageenan (50 µl intraplantar) and tested 3 h and 24 h after injection using thermal (plantar test) and mechanociceptive tests (von Frey). The rats were divided into the following groups: (a) young rats infiltrated for the first time at 12 weeks of age and re-infiltrated at 15 and 17 weeks; (b) adult rats infiltrated for the first time at 28 weeks of age and re-infiltrated at 44 and 56 weeks; and (c) old rats infiltrated for the first time at 56 weeks of age and re-infiltrated at 72 weeks. The rats tested for the first time at 12 and 56 weeks of age showed hyperalgesia due to carrageenan infiltration at 3 h and 24 h after injection. This result showed that old rats maintain the same antialgesic response due to inflammation. However, when the injection was repeated in the three age groups, the latency to the thermal and mechanociceptive responses at 3 h is increased when compared to animals exposed for the first time to inflammation. The response to thermal and mechanociception in old rats is the same as in young animals as long as the nociceptive stimulus is not repeated. The repetition of the stimulus produces changes compatible with desensitization of the response and evidences the significance of algesic stimulus repetition in the same individual rather than the age of the individual.

Taurine enhances antinociception produced by a COX-2 inhibitor in an inflammatory pain model.

The temporal activation of the sensory systems, especially in pain, determines intermediate states that define the future of the response to sensory stimulation. In this work, we interfere pharmacologically with those states that produce peripheral and central sensitisation after an acute inflammatory process, inhibiting at the periphery the COX-2 with celecoxib and using taurine (glycine A receptor agonist) for central pain relief. We tested the paw withdrawal reflex latencies to thermo- and mechanonociception after the induction of an acute inflammatory process with carrageenan. Celecoxib at low doses [0.13 and 1.3 mg/kg, intraperitoneal (i.p.)] in combination with taurine (300 mg/kg, i.p.) produces a decrease of the nociceptive response in thermo- and mechanonociception, as compared with the effect of both drugs alone. We propose that the enhancement of the analgesic effect of celecoxib in combination with taurine could be due the simultaneous action of these drugs at both, peripheral and central levels.

Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours.

Injury to the insular cortex in humans produces a lack of appropriate response to pain. Also, there is controversial evidence on the lateralization of pain modulation. The aim of this study was to test the effect of insular cortex lesions in three models of pain in the rat. An ipsilateral, contralateral or bilateral radiofrequency lesion of the rostral agranular insular cortex (RAIC) was performed 48h prior to acute, inflammatory or neuropathic pain models in all the experimental groups. Acute pain was tested with paw withdrawal latency (PWL) after thermal stimulation. Inflammation was induced with carrageenan injected in the paw and PWL was tested 1h and 24h afterwards. Neuropathic pain was tested after ligature of the sciatic nerve by measuring mechanical nociceptive response after stimulation with the von Frey filaments. Another model of neuropathy consisted of thermo stimulation followed by right sciatic neurectomy prior to the recording of autotomy behaviour. Acute pain was not modified by the RAIC lesion. All the RAIC lesion groups showed diminished pain-related behaviours in inflammatory (increased PWL) and neuropathic models (diminished mechanical nociceptive response and autotomy score). The lesion of the RAIC produces a significant decrease in pain-related behaviours, regardless of the side of the lesion. This is a clear evidence that the RAIC plays an important role in the modulation of both inflammatory and neuropathic - but not acute - pain.