Systematic Review and Metanalysis of the Expression of Blood-Based and Cerebrospinal Fluid-Based Biomarkers Related to Inflammatory Mediators in Neuropathic Pain.

BACKGROUND: The understanding of neuropathic pain remains incomplete, highlighting the need for research on biomarkers for improved diagnosis and treatment. This review focuses on identifying potential biomarkers in blood and cerebrospinal fluid for neuropathic pain in different neuropathies. METHODS: Searches were performed in six databases: PubMed, Web of Science, Scopus, Cochrane Library, EMBASE, and CINAHL. Included were observational studies, namely cross-sectional, cohort, and case-control, that evaluated quantitative biomarkers in blood or cerebrospinal fluid. Data were qualitatively synthesized, and meta-analyses were conducted using R. The study is registered with PROSPERO under the ID CRD42022323769. RESULTS: The literature search resulted in 16 studies for qualitative and 12 for quantitative analysis, covering patients over 18 years of age with painful neuropathies. A total of 1403 subjects were analyzed, identifying no significant differences in levels of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) between patients with and without pain. Despite the high inter-rater reliability and adequate bias assessment, the results suggest negligible differences in inflammatory biomarkers, with noted publication bias and heterogeneity among studies, indicating the need for further research. CONCLUSIONS: Our review underscores the complex nature of neuropathic pain and the challenges in identifying biomarkers, with no significant differences found in CRP, IL-6, and TNF-alpha levels between patients with and without pain. Despite methodological robustness, the results are limited by publication bias and heterogeneity. This emphasizes the need for further research to discover definitive biomarkers for improved diagnosis and personalized treatment of neuropathic pain.

Adults with excess weight or obesity, but not with overweight, report greater pain intensities than individuals with normal weight: a systematic review and meta-analysis.

Context: Over 1.9 billion adult people have overweight or obesity. Considered as a chronic disease itself, obesity is associated with several comorbidities. Chronic pain affects approximately 60 million people and its connection with obesity has been displayed in several studies. However, controversial results showing both lower and higher pain thresholds in subjects with obesity compared to individuals with normal weight and the different parameters used to define such association (e.g., pain severity, frequency or duration) make it hard to draw straight forward conclusions in the matter. The objective of this article is to examine the relationship between overweight and obesity (classified with BMI as recommended by WHO) and self-perceived pain intensity in adults. Methods: A literature search was conducted following PRISMA guidelines using the databases CINAHL, Cochrane Library, EMBASE, PEDro, PubMed, Scopus and Web of Science to identify original studies that provide BMI values and their associated pain intensity assessed by self-report scales. Self-report pain scores were normalized and pooled within meta-analyses. The Cochrane's Q test and I2 index were used to clarify the amount of heterogeneity; meta-regression was performed to explore the relationship between each outcome and the risk of bias. Results: Of 2194 studies, 31 eligible studies were identified and appraised, 22 of which provided data for a quantitative analysis. The results herein suggested that adults with excess weight (BMI ≥ 25.0) or obesity (BMI ≥ 30.0) but not with overweight (pre-obesity) alone (BMI 25.0-29.9), are more likely to report greater intensities of pain than individuals of normal weight (BMI 18.5-24.9). Subgroup analyses regarding the pathology of the patients showed no statistically significant differences between groups. Also, influence of age in the effect size, evaluated by meta-regression, was only observed in one of the four analyses. Furthermore, the robustness of the findings was supported by two different sensitivity analyses. Conclusion: Subjects with obesity and excess weight, but not overweight, reported greater pain intensities than individuals with normal weight. This finding encourages treatment of obesity as a component of pain management. More research is required to better understand the mechanisms of these differences and the clinical utility of the findings. Systematic Review Registration: https://doi.org/10.17605/OSF.IO/RF2G3, identifier OSF.IO/RF2G3.

Short-term stress significantly decreases morphine analgesia in trigeminal but not in spinal innervated areas in rats.

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10-20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6-5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia.

Antinociceptive and modulatory effect of pathoplastic changes in spinal glia of a TLR4/CD14 blocking molecule in two models of pain in rat.

The role of spinal glia in the development and maintenance of chronic pain has become over the last years a subject of increasing interest. In this regard, toll-like receptor 4 (TLR4) signaling has been proposed as a major trigger mechanism. Hence, in this study we explored the implications of TLR4 inhibition in the periphery and primarily in the CNS, focusing on the impact this inhibition renders in pain development and glia activation in the dorsal horn in two models of pain. Making use of a synthetic cluster of differentiation 14 (CD14)/TLR4 antagonist, the effect of TLR4 blockade on tactile allodynia and heat hyperalgesia was evaluated in osteoarthritic and postoperative rat models. An in vitro parallel artificial membrane permeation assay was performed to determine the proneness of the drug to permeate the blood-brain barrier prior to systemic and central administration. Findings suggest a dominant role of peripheral TLR4 in the model of incisional pain, whilst both peripheral and central TLR4 seem to be responsible for osteoarthritic pain. That is, central and peripheral TLR4 may be differently involved in the etiopathology of diverse types of pain what potentially seems a promising approach in the management of pain.

SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner.

The serum and glucocorticoid-regulated kinase 1 (SGK1) is a widely expressed protein in the Central Nervous System (CNS), involved in regulating the activity of a wide variety of ion channels and transporters and physiological functions, such as neuronal excitability. SGK1.1 is a neuronal splice isoform of SGK1, expressed exclusively in the CNS, distributed in brain and cerebellum, that decreases neuronal excitability via up-regulation of M-current, linked to Kv7.2/3 potassium channels. Strategies to maintain increased SGK1.1 activity could be helpful in decreasing neuronal hyperexcitability, as occurs in neuropathic pain. Transgenic mice overexpressing SGK1.1 (B6.Tg.sgk1) offer a particularly relevant opportunity to assess the physiological involvement of this protein in nociception. Behavior and physiological nociception were evaluated in male and female B6.Tg.sgk1 and wild-type mice (B6.WT), characterizing nociceptive thresholds to different nociceptive stimuli (thermal, chemical and mechanical), as well as the electrophysiological properties of cutaneous sensory Aδ-fibres isolated from the saphenous nerve. The acute antinociceptive effect of morphine was also evaluated. Compared with B6.WT animals, male and female B6.Tg.sgk1 mice showed increased spontaneous locomotor activity. Regarding nociception, there were no differences between transgenic and wild-type mice in heat, chemical and mechanical thresholds, but interestingly, male B6.Tg.sgk1 mice were less sensitive to cold stimulus; B6.Tg.sgk1 animals showed lower sensitivity to morphine. Electrophysiological properties of cutaneous primary afferent fibres were maintained. This is the first demonstration that the SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner. B6.Tg.sgk1 mice offer a particularly relevant opportunity to further analyze the involvement of this protein in nociception, and studies in models of chronic, neuropathic pain are warranted.

Monoclonal Antibodies for Chronic Pain Treatment: Present and Future.

Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways that look to be very effective and promising as a novel therapy in pain management. Thus, there are mAbs against tumor necrosis factor (TNF), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), or interleukin-6 (IL-6), among others, which are already recommended in the treatment of chronic pain conditions such as osteoarthritis, chronic lower back pain, migraine, or rheumatoid arthritis that are under preclinical research. This narrative review summarizes the preclinical and clinical evidence supporting the use of these agents in the treatment of chronic pain.

TLR4 Antagonism Reduces Movement-Induced Nociception and ATF-3 Expression in Experimental Osteoarthritis.

INTRODUCTION: Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the detection of pathogen-associated molecular patterns (PAMPs), but also a "danger-sensing" receptor that recognizes host-derived endogenous molecules called damage-associated molecular patterns (DAMPs). The involvement of TLR4 in rheumatic diseases is becoming evident, as well as its potential role as a target for therapeutic intervention. Moreover, increasing evidence also suggests that TLR4 is implicated in chronic pain states. Thus, in this study, we evaluated whether a systemic administration of a synthetic antagonist of TLR4 (TLR4-A1) could decrease nociception and cartilage degradation in experimental osteoarthritis (OA). Furthermore, as the activation transcription factor (ATF)-3 serves as a negative regulator for TLR4-stimulated inflammatory response, we also evaluated the effect of TLR4 inhibition on ATF-3 expression in primary afferent neurons at the dorsal root ganglia (DRG). METHODS: OA was induced in adult male Wistar rats through an intra-articular injection of 2 mg of sodium mono-iodoacetate (MIA) into the left knee. From days 14 to 28 after OA induction, animals received an intraperitoneal injection of either TLR4-A1 (10 mg/kg) or vehicle. Movement- and loading-induced nociception was evaluated in all animals, by the Knee-Bend and CatWalk tests, before and at several time-points after TLR4-A1/vehicle administration. Immunofluorescence for TLR4 and ATF-3 was performed in L3-L5 DRG. Knee joints were processed for histopathological evaluation. RESULTS: Administration of TLR4-A1 markedly reduced movement-induced nociception in OA animals, particularly in the Knee-Bend test. Moreover, the increase of ATF-3 expression observed in DRG of OA animals was significantly reduced by TLR4-A1. However, no effect was observed in cartilage loss nor in the neuronal cytoplasmic expression of TLR4 upon antagonist administration. CONCLUSION: The TLR4 antagonist administration possibly interrupts the TLR4 signalling cascade, thus decreasing the neurotoxic environment at the joint, which leads to a reduction in ATF-3 expression and in nociception associated with experimental OA.

Clusterin: Always protecting. Synthesis, function and potential issues.

In the last years, clusterin, a challenging and paradoxical apolipoprotein, has been of growing interest amongst a rising number of scientists. This enigmatic protein is present in all fluids of the organism besides within the intracellular matrix, and it plays diverse, and at times contrary, roles in a growing number of pathologies. It seems to vary its location and function to assure cellular survival being cytoprotective hence its significance in neuroprotection and cancer along with chemotherapy resistance. However, it can also lead to cellular arrest and its modulation to apoptosis. Additionally, it has been described to modulate pain, as well as linked to inflammation, cardioprotection, satiety and hunger, and possibly to addictive behaviour development. Thus, it has been postulated to be used both as a biomarker and a very explorable new therapeutic target for several conditions.

Sciatic Nerve Ligation Downregulates Mitochondrial Clusterin in the Rat Prefrontal Cortex.

The concentration of the multifunctional protein clusterin is reduced in the plasma of subjects with degenerative scoliosis (DS) and carpal tunnel syndrome (CTS) but elevated in the cerebrospinal fluid of neuropathic pain patients successfully treated with spinal cord stimulation. The present work tries to increase the knowledge of pain-associated changes of plasma and brain clusterin by using an animal model of neuropathy. We studied the effects of sciatic nerve ligation on mechanical allodynia (von Frey test), anxiety (elevated plus maze test), plasma clusterin (enzyme-linked immunosorbent assay) and clusterin expression in the nucleus accumbens (NAC) and prefrontal cortex (PFC) of adult male Wistar rats (western blot). The possible modulatory role of high fat (HF) dieting was also studied, bearing in mind that obesity has been also reported to influence nociception, clusterin levels and prefrontal cortex activation. Animals with nerve ligation showed mechanical allodynia, anxiety and a marked downregulation of clusterin in the mitochondrial fraction of the prefrontal cortex. Animals fed on HF also exhibited a slight increase of the sensitivity to mechanical stimuli and anxiety; however, the diet did not potentiate the effects of nerve ligation. The results did not confirm a parallelism between neuropathy, obesity and alterations of plasma levels of clusterin, but strongly suggest that the protein could be involved in the functional reorganization of the prefrontal cortex which has been recently reported in chronic pain conditions.

Maternal separation affects the electrophysiological properties of Aδ-fibres and nociceptive behaviours in male and female mice.

AIM: Early life adverse effects have been associated with an increased risk of suffering pain syndromes in adulthood. Although animal models are of great importance to study modifications of pain sensitivity, up to date the results obtained are contradicting due to the varied methodologies used. Therefore, the aim of the present study was to characterise, as a whole, possible modifications in visceral and somatic nociceptive responses in male and female ICR mice, submitted to two different protocols of maternal separation (MS), and possible modifications in the electrophysiological properties of peripheral nociceptive Aδ-primary afferents. MAIN METHODS: Male and female mice were submitted to 3 or 4-8 hr of daily MS from postnatal day (PND) 2-17 and early weaned. On PND 67 von Frey, hot plate and writhing tests were performed. Afterwards electrophysiological recordings were carried out, using the in vitro skin-saphenous nerve preparation in males. KEY FINDINGS: The short separation protocol of MS did not modify nociceptive sensitivity; but when mice were separated from their dams for the long separation, mechanical pain thresholds were modified in male and female mice and visceral nociception was increased in female mice. Electrophysiological recordings showed that cutaneous Aδ-fibres were sensitised and their mechanotransduction properties were altered in both MS protocols. SIGNIFICANCE: Although MS increases the activity and the mechanosensitivity of cutaneous Aδ-afferent fibres at both short and long periods of separation, only the longer interval of time induces nociceptive sensitivity alterations during adulthood. These results highlight the possible influence of a stress free environment during childhood to reduce nociceptive alterations in adulthood.

Toll-like receptor 4: A promising crossroads in the diagnosis and treatment of several pathologies.

Toll-like receptor 4 (TLR4) is expressed in a wide variety of cells and is the central component of the mammalian innate immune system. Since its discovery in 1997, TLR4 has been assigned an ever-increasing number of functions that extend from pathogen recognition to tissue damage identification and promotion of the intrinsic "damage repair response" in pain, intestinal, respiratory and vascular disorders. Precisely, the finding of conserved sequence homology among species along with the molecular and functional characterisation of the TLR4 gene enabled researchers to envisage a common operating system in the activation of innate immunity and the initiation of plastic changes at the onset of chronic pain. Malfunctioning in other conditions was conceived in parallel. In this respect, "pivot" proteins and pathway redundancy are not just evolutionary leftovers but essential for normal functioning or cell survival. Indeed, at present, TLR4 single nucleotide polymorphisms (SNP) and their association with certain dysfunctions and diseases are being confirmed in different pools of patients. However, despite its ability to trigger pathogen infection or alternatively tissue injury communications to immune system, TLR4 targeting might not be considered a panacea. This review article represents a compilation of what we know about TLR4 from clinics and basic research on the 20th anniversary of its discovery. Understanding how to fine-tune the interaction between TLR4 and its specific ligands may lead in the next decades to the development of promising new treatments, reducing polypharmacy and probably having an impact on drug use in numerous pathologies.

Animal models in the study and treatment of orofacial pain.

BACKGROUND: Pain is one of the first causes of medical consultation in the world and by extension of dental consultation too. Orofacial pain comprehends the oral and facial regions including teeth, oral mucosa, gingiva, tongue and lips, but also the muscles of the jaw and neck, the temporomandibular joint, face, head and neck. Despite its highly estimated prevalence, it appears controversial and hard to quantify given the lack of common criteria to select the population under study and the difficulties to classify the different types of pain. Although for many patients the problem eventually fades after tissue healing, certain sub-chronic and chronic pain conditions remain notoriously undertreated. In this respect, animal models can be of great help. MATERIAL AND METHODS: A systematic search was conducted in PubMed-Medline with appropriate keywords: orofacial pain, prevalence and dentist. Seven groups were generated and a second search based on each of these groups and on animal models was made. Search was restricted to English and Spanish, but no time restriction was applied. RESULTS: There are as yet few experimental models of orofacial pain: there hardly exists no other than trigeminal nerve injury for neuropathic pain, a bunch of oral squamous cell carcinoma models (mainly referred to the tongue) for cancer pain and none for the painful swelling of salivary glands. Similarly occurs for the burning mouth syndrome. A few more exist for inflammatory odontalgiae, aphthae, joint, myofascial and muscle inflammatory pains, although scarcely diverse as regards the nature of the noxious stimulus. CONCLUSIONS: Given the relevance of envisaging the mechanistic of the various types of orofacial pain, new experimental models are needed on the basis of the dentist's perspective for their correct management. Key words:Orofacial pain, neuralgia, odontalgia, oral cancer, animal models.

Comparison of the antinociceptive profiles of morphine and oxycodone in two models of inflammatory and osteoarthritic pain in rat.

Oxycodone and morphine are two opioid drugs commonly used for the treatment of moderate to severe pain. However, their use in the management of noncancer pain remains a controversial issue and, in this respect, the evidence on their effectiveness and safety, particularly in osteoarthritis, is being questioned. In order to analyse their analgesic profile, two different pain models in rats were used: the formalin-induced inflammatory pain and the monosodium iodoacetate (MIA)-induced knee osteoarthritic pain. Drugs were administered systemically (i.p.) and their antinociceptive effect and potency were assessed. In the formalin test, both morphine and oxycodone produced a dose-dependent antinociceptive effect, but oxycodone outdid morphine in terms of effectiveness and potency (nearly two times) in the early (acute nociceptive) as in the late phase (inflammatory). In the osteoarthritis model, both drugs reduced movement-evoked pain (knee-bend test), mechanical allodynia (von Frey test) and heat hyperalgesia (Plantar test). Pretreatment with naloxone and naloxone methiodide reduced morphine and oxycodone effects. Peripheral mu-opioid receptors play a crucial role in the antinociceptive effect of both drugs on movement-evoked pain and heat hyperalgesia, but not on tactile allodynia. The main finding of our study is that oxycodone has a better antinociceptive profile in the inflammatory and osteoarthritic pain, being more effective than morphine at 14 days post-MIA injection (phase with neuropathic pain); it overcame the morphine effect by improving the movement-induced pain, tactile allodynia and heat hyperalgesia. Therefore, oxycodone could be an interesting option to treat patients suffering from knee osteoarthritis when opioids are required.

May a sigma-1 antagonist improve neuropathic signs induced by cisplatin and vincristine in rats?

BACKGROUND: The antineoplastic drugs cisplatin and vincristine induce peripheral neuropathies. The sigma-1 receptor (σ1R) is expressed in areas of pain control, and its blockade with the novel selective antagonist MR-309 has shown efficacy in nociceptive and neuropathic pain models. Our goal was to test whether this compound reduces neuropathic signs provoked by these antitumoural drugs. METHODS: Rats were treated with cisplatin or vincristine to induce neuropathies. The effects of acute or repeated administration of MR-309 were tested on mechanical and thermal sensitivity, electrophysiological activity of Aδ-primary afferents in the rat skin-saphenous nerve preparation, and gastrointestinal or cardiovascular functions. RESULTS: Rats treated with antitumourals developed tactile allodynia, while those treated with vincristine also developed mechanical hyperalgesia. These in vivo modifications correlated with electrophysiological hyperactivity (increased spontaneous activity and hyperresponsiveness to innocuous and noxious mechanical stimulation). Animals treated with cisplatin showed gastrointestinal impairment and those receiving vincristine showed cardiovascular toxicity. A single dose of MR-309 strongly reduced both nociceptive behaviour and electrophysiological changes. Moreover, its concomitant administration with the antitumourals blocked the development of neuropathic symptoms, thus restoring mechanical sensitivity, improving the impairment of feeding behaviour and gastrointestinal transit in the cisplatin-treated group along with ameliorating the altered vascular reactivity recorded in rats treated with vincristine. CONCLUSION: σ1R antagonist, MR-309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects. SIGNIFICANCE: σ1R antagonism could be an interesting and new option to palliate antitumoural neuropathies.

The role of Omega-3 and Omega-9 fatty acids for the treatment of neuropathic pain after neurotrauma.

Omega-3 polyunsaturated fatty acids (PUFAs), such as docosaexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mediate neuroactive effects in experimental models of traumatic peripheral nerve and spinal cord injury. Cellular mechanisms of PUFAs include reduced neuroinflammation and oxidative stress, enhanced neurotrophic support, and activation of cell survival pathways. Bioactive Omega-9 monounsaturated fatty acids, such as oleic acid (OA) and 2-hydroxy oleic acid (2-OHOA), also show therapeutic effects in neurotrauma models. These FAs reduces noxious hyperreflexia and pain-related anxiety behavior following peripheral nerve injury and improves sensorimotor function following spinal cord injury (SCI), including facilitation of descending inhibitory antinociception. The relative safe profile of neuroactive fatty acids (FAs) holds promise for the future clinical development of these molecules as analgesic agents. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.

Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells.

Spinal glial activation contributes to the development and maintenance of chronic pain states, including neuropathic pain of diverse etiologies. Cannabinoid compounds have shown antinociceptive properties in a variety of neuropathic pain models and are emerging as a promising class of drugs to treat neuropathic pain. Thus, the effects of repeated treatment with WIN 55,212-2, a synthetic cannabinoid agonist, were examined throughout the development of paclitaxel-induced peripheral neuropathy. Painful neuropathy was induced in male Wistar rats by intraperitoneal (i.p.) administration of paclitaxel (1mg/kg) on four alternate days. Paclitaxel-treated animals received WIN 55,212-2 (1mg/kg, i.p.) or minocycline (15 mg/kg, i.p.), a microglial inhibitor, daily for 14 days, simultaneous with the antineoplastic. The development of hypersensitive behaviors was assessed on days 1, 7, 14, 21 and 28 following the initial administration of drugs. Both the activation of glial cells (microglia and astrocytes) at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Similar to minocycline, repeated administration of WIN 55,212-2 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel-treated rats. WIN 55,212-2 treatment also prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines (interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α). Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of WIN 55,212-2, probably via glial cells reactivity inactivation, on the development of this neuropathy.

Antinociceptive effect of three common analgesic drugs on peripheral neuropathy induced by paclitaxel in rats.

Nowadays, there are no validated drugs to control the neuropathic pain induced by paclitaxel, one of the most effective antineoplastic drugs. The aim was to study the involvement of opioid and NMDA receptor on established paclitaxel-induced pain, testing three common analgesics drugs morphine, ketamine and methadone. Animals received four intraperitoneal (i.p.) injections on alternate days of paclitaxel (1mg/kg). Three weeks later, animals showed a mechanical and heat allodynia/hyperalgesia. Morphine (1, 2.5, 5 and 10mg/kg) abolished the reduction in the mechanical and thermal withdrawal thresholds in a dose dependent manner. This effect was blocked by naloxone. Only highest dose of ketamine (50mg/kg) was able to increase the mechanical and thermal threshold and returned to basal values. Subanalgesic doses of morphine (1mg/kg) and ketamine (12.5mg/kg) produced an additive effect on heat hyperalgesia reaching an antinociceptive effect. This combination did not induce any change on tactile allodynia. Methadone (2.5 and 5mg/kg) produced an analgesic effect that was completely antagonized by naloxone in both tests. Our results confirm that: the activation of opioids receptor produced analgesia; the blockade of NMDA receptors produce antinociception but at high doses with motor impairments and low doses of ketamine enhancing the effect of opioids.

Antinociceptive effect of the cannabinoid agonist, WIN 55,212-2, in the orofacial and temporomandibular formalin tests.

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.