minocycline and Pain

Tetracyclines are a class of broad-spectrum bacteriostatic antibiotics used to treat many infections, including methicillin-resistant Staphylococcus aureus (MRSA), acne, pelvic inflammatory disease, chlamydial infections, and a host of zoonotic infections. These drugs work by inhibiting protein synthesis in bacterial ribosomes, specifically by disallowing aminoacyl-tRNA molecules from binding to the ribosomal acceptor sites. While rare, tetracycline antibiotics, particularly minocycline and doxycycline, are associated with an increased risk of developing esophageal perforation and pseudotumor cerebri (PTC, or idiopathic intracranial hypertension). Since tetracyclines are a commonly prescribed class of medications, especially in adolescents for acne treatment, it is important for clinicians to appreciate significant side effects that can result in morbidity and mortality. This paper aims to consolidate and to emphasize current research on the association between tetracycline antibiotics and the development of esophageal perforation, and PTC. PTC is a neurological syndrome consisting of increased intracranial pressure, headache, and vision changes without evidence of the contributing source, such as mass lesion, infection, stroke, or malignancy. Esophageal perforation, while rare, can be the result of pill esophagitis. Pill-induced injuries occur when caustic medicinal pills dissolve in the esophagus rather than in the stomach. Most patients experience only self-limited pain (retrosternal burning discomfort, heartburn, dysphagia, or odynophagia), but hemorrhage, stricture, and perforation may occur. Tetracycline use can lead to pill esophagitis. In summary, clinicians should appreciate the potential risks of tetracycline compounds in clinical practice.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Doxycycline; Esophageal Perforation; Esophagitis; Humans; Methicillin-Resistant Staphylococcus aureus; Minocycline; Pain; Pseudotumor Cerebri; Tetracycline

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Dendrobium; Lipopolysaccharides; Mice; Nitric Oxide; Pain; Stilbenes

Patients with multiple myeloma (MM) experience substantial cancer/treatment-related symptom burden during maintenance therapy. This is a phase II randomized, double-blinded, placebo-controlled clinical trial to examine the effect of minocycline for symptom reduction by its potential anti-inflammatory effect.. Eligible MM patients for maintenance therapy were randomized to receive minocycline (100 mg twice daily) or placebo. The MD Anderson Symptom Inventory for MM (MDASI-MM) was used to assess multiple symptoms weekly during the trial. Clinician-rated toxicities and blood samples were prospectively collected. The effect size, area under the curve (AUC), and t tests were used to determine the symptom burden between treatment groups and identify the 5 most-severe MDASI-MM symptoms. The longitudinal analysis compared the changes in symptom severity and associated inflammatory markers between groups over time.. Sixty-nine evaluable MM patients (33 from the intervention group and 36 from the placebo group) were included. No grade 3+ adverse events related to study medication were noted. The AUCs for the 5 worst MDASI-MM symptoms (fatigue, pain, disturbed sleep numbness/tingling, and drowsiness) were not significantly different between two arms. Regardless of group assignment, pain reduction was positively associated with decreased serum levels of soluble tumor necrosis factor-α receptors 1 and 2 during therapy (all P < 0.05).. This pPhase II randomized study observed no statistically significant positive signal impact from minocycline on symptom reduction or inflammatory markers during maintenance therapy for MM, although using minocycline was feasible and had a low toxicity profile.

Topics: Biomarkers; Double-Blind Method; Fatigue; Humans; Minocycline; Multiple Myeloma; Pain

Although it is well known that patients with advanced pancreatic cancer (PC) experience significant symptom burden, few strategies for effective symptom intervention are available for them.. To investigate the efficacy of minocycline, an anti-inflammatory agent, for symptom reduction in patients with advanced PC.. We conducted Phase II, randomized, and placebo-controlled trial to obtain preliminary estimates of the effects on symptom reduction with 100 mg of minocycline or placebo given twice a day. Eligible patients had diagnosed advanced PC and were scheduled for standard chemotherapy. Patient-reported symptoms were measured weekly during the eight-week trial using the MD Anderson Symptom Inventory (MDASI) module in patients with gastrointestinal cancer. The primary outcome measure was the area under the curve values of the five most severe symptoms in the two arms.. Of the 44 patients recruited, 31 (71%) were evaluable for the primary efficacy analysis, with 18 received minocycline and 13 placebo. Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were the most severe symptoms reported by both groups. No significant differences in area under the curve values over time between the study arms were found for the composite MDASI score or single-item scores of the five most severe MDASI items. No treatment-related deaths were reported, and no Grade 3-4 toxicities were observed.. Minocycline is safe for use in patients receiving treatment for PC. There is no observed symptom reduction with minocycline on the major symptom burden associated with advanced PC compared with placebo. Attrition because of rapid disease progression impacted the study significantly.

Topics: Double-Blind Method; Fatigue; Humans; Minocycline; Pain; Pancreatic Neoplasms

Local/systemic symptoms during cancer therapy may be exacerbated by dysregulated inflammation and its downstream toxic effects. Minocycline can suppress proinflammatory cytokine release; therefore, we investigated its potential to reduce patient-reported symptom severity during radiotherapy (RT) for head and neck cancer (HNC).. Eligible patients for this blinded, placebo-controlled trial were adults with T0-3, N-any, and M0 HNC receiving single-modality RT. Participants were randomized 1:1 to either minocycline (200 mg/day) or placebo during RT. The primary endpoint was the area under the curve (AUC) of 5 prespecified symptoms (pain, fatigue, disturbed sleep, poor appetite, difficulty swallowing/chewing) during RT, assessed with the MD Anderson Symptom Inventory for HNC (MDASI-HN).. We analyzed data from 20 evaluable patients per arm. Overall, 75% had oropharyngeal cancer and 78% were male. No grade 3+ adverse events potentially related to study medication were observed. Two minocycline patients required a feeding tube during RT vs 5 placebo patients (P = 0.21). The average daily AUC during RT for the 5 MDASI-HN symptoms was 3.1 (SD = 1.0) for minocycline and 3.7 (SD = 1.7) for placebo (P = 0.16); the 0.37 effect size was less than our 0.70 target. AUC comparisons for several individual symptoms and symptom interference favored minocycline but were not statistically significant. The greatest numerical differences occurred for systemic symptoms, larger toward treatment end, and in early post-RT recovery.. Minocycline was feasible, well tolerated, and achieved a positive signal toward reducing patient-reported symptom severity during RT for HNC, particularly for systemic symptoms. This justifies additional study and informs future trial design.

Topics: Aged; Combined Modality Therapy; Deglutition Disorders; Fatigue; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Minocycline; Pain; Radiodermatitis; Sleep Wake Disorders; Treatment Outcome

Minocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.. In this double-blind, randomized human laboratory study, 20 participants were randomized to either minocycline (200 mg/day) or placebo treatment for 15 days. The study had three test sessions (days 1, 8, and 15 of treatment) and one follow-up visit 1 week after the end of treatment. In each test session, participants were assessed on several subjective and cognitive measures, followed by assessment of pain sensitivity using the Cold Pressor Test (CPT). Daily surveys and cognitive measures using Ecological Momentary Assessment (EMA) were also collected four times a day on days 8 through 14 of treatment, and proinflammatory serum cytokines were assessed before and on the last day of treatment.. Minocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.. While these findings do not support minocycline's effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.

Topics: Adult; Analgesics, Opioid; Behavior, Addictive; Double-Blind Method; Drug Tolerance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Minocycline; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Young Adult

Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes.. This study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg.. Eighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (-38% in affected leg, 95% CI for difference -19% to -52%). Both hand dominance and sex were significant covariates of response to capsaicin.. It cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain.

Topics: Adult; Analysis of Variance; Capsaicin; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; gamma-Aminobutyric Acid; Humans; Hyperalgesia; Injections, Intradermal; Male; Middle Aged; Minocycline; Pain; Pregabalin; Sciatica; Time Factors; Treatment Outcome

Between February 1994 and November 1998, 56 oncology patients infected with vancomycin-resistant enterococci (VRE) were treated with quinopristin-dalfopristin (Q-D) plus minocycline (MIN). Infections included bacteremia, urinary tract infection, pneumonia, and wound infection. The response rate was 68%, and the most frequent adverse event was arthralgia or myalgia (36%). Q-D-MIN is effective for VRE infection in cancer patients but is associated with a substantial frequency of arthralgia or myalgia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antineoplastic Agents; Child; Drug Therapy, Combination; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Female; Gram-Positive Bacterial Infections; Humans; Immunity; Male; Middle Aged; Minocycline; Neoplasms; Pain; Vancomycin Resistance; Virginiamycin

Alveolar osteitis (AO) is one of the most commonly encountered complication following tooth extraction, however, to date there is no standard methods of prevention and treatment. The study aims to investigate the efficiency of minocycline hydrochloride ointment (MHO) for the treatment of alveolar osteitis compared with traditional treatment with iodoform gauze (IG).. STROBE checklist was followed to report this study. All patients underwent tooth extraction either in our department or other hospitals, whom presented with postoperative pain, were screened out to meet the inclusion and exclusion criteria of this study about AO. Patients who fulfilled the inclusion criteria were enrolled in our prospective cohort study, and MHO or IG was administered. The Visual analog scale scores were used to assess the pain score of patients. The healing status of the extraction sockets was followed up. Differences in responses between groups were analyzed using Mann-Whitney U tests. Chi-square test was performed to explore the differences in the teeth position of AO.. Of 41,371 patients underwent tooth extraction with post-operative follow-up in our departments, only 20 patients (0.05%) suffered from AO. 31 patients with AO, whose teeth were extracted in other places, were also enrolled. The incidence of AO was significantly higher in third molars than other teeth (P < 0.01). In 28 patients that were treated with MHO, the pain was relieved substantially on day 3 and almost painless on day 7. And only 25% of cases required dressing change more than once. Whilst 23 patients treated with IG, the pain was relieved on day 5, and 56.5% of cases required multiple dressing change. The difference between the two groups of VAS scores had statistical significance during treatment at 8 h, 24 h, 3d, 5d, and 7d. No allergic reaction or further infection occurred.. MHO has a safer and higher therapeutic effect in the treatment of AO compared with traditional treatment with IG. MHO may become a preferred treatment modality for AO.

Topics: Dry Socket; Humans; Minocycline; Molar, Third; Ointments; Pain; Prospective Studies; Tooth Extraction; Tooth, Impacted

Remnant-preserving anterior cruciate ligament reconstruction (ACLR) should have advantages for postoperative remodeling and proprioception. However, it has been suggested that the larger diameter of the graft tends to lead to impingement phenomena with a higher rate of cyclops lesions. The aim of this work was to find out whether the remnant-preserving ACLR actually leads to an increased rate of range of motion restraints compared to the remnant-sacrificing technique.. Patients, who fulfilled the inclusion criteria, were followed up for one year after surgery. The primary endpoint was arthrolysis due to extension deficit or cyclops syndrome. Secondary outcome measures were pain (NRS), knee function (KOOS), patient satisfaction and return to sports rate.. One hundred and sixty-four patients were included in the study, 60 of whom received the "remnant augmentation" procedure (group 1). In the remnant augmentation group, one cyclops resection was performed, whereas in the non-remnant augmentation group three cyclops lesion resections had to be performed (odds ratio 0.6). There was no difference between the groups in pain (NRS) and knee function (KOOS) and patient satisfaction. The return to sports rate after one year was higher in the remnant augmentation group.. Patients who have undergone the sparing "remnant augmentation" ACLR have no increased risk of cyclops lesion formation or extension deficit in the first year after surgery. An improvement of the proprioceptive abilities by remnant augmentation ACLR should be investigated in further studies.. III (prospective cohort study).

Topics: Anterior Cruciate Ligament; Humans; Minocycline; Pain; Prospective Studies; Treatment Outcome

Opioids are among the most effective and widely prescribed medications for the treatment of pain following spinal cord injury (SCI). Spinally-injured patients receive opioids within hours of arrival at the emergency room, and prolonged opioid regimens are often employed for the management of post-SCI chronic pain. However, previous studies in our laboratory suggest that the effects of opioids such as morphine may be altered in the pathophysiological context of neurotrauma. Specifically, we have shown that morphine administration in a rodent model of SCI increases mortality and tissue loss at the injury site, and decreases recovery of motor and sensory function, and overall health, even weeks after treatment. The literature suggests that opioids may produce these adverse effects by acting as endotoxins and increasing glial activation and inflammation. To better understand the effects of morphine following SCI, in this study we used flow cytometry to assess immune-competent cells at the lesion site. We observed a morphine-induced increase in the overall number of CD11b+ cells, with marked effects on microglia, in SCI subjects. Next, to investigate whether this increase in the inflammatory profile is necessary to produce morphine's effects, we challenged morphine treatment with minocycline. We found that pre-treatment with minocycline reduced the morphine-induced increase in microglia at the lesion site. More importantly, minocycline also blocked the adverse effects of morphine on recovery of function without disrupting the analgesic efficacy of this opioid. Together, our findings suggest that following SCI, morphine may exacerbate the inflammatory response, increasing cell death at the lesion site and negatively affecting functional recovery.

Topics: Analgesics, Opioid; Animals; Inflammation; Macrophages; Male; Microglia; Minocycline; Morphine; Pain; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries

Topics: Animals; Enzyme Inhibitors; Female; Hyperalgesia; Imidazoles; Interferon Regulatory Factors; Male; Microglia; Minocycline; Neurons; Pain; Pain Threshold; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Sex Factors; Spinal Cord

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of many antineoplastic agents. Patients treated with chemotherapy often report pain and paresthesias in a "glove-and-stocking" distribution. Diverse mechanisms contribute to the development and maintenance of CIPN. However, the role of spinal microglia in CIPN is not completely understood. In this study, cisplatin-treated mice displayed persistent mechanical allodynia, sensory deficits and decreased density of intraepidermal nerve fibers (IENFs). In the spinal cord, activation of microglia, but not astrocyte, was persistently observed until week five after the first cisplatin injection. Additionally, mRNA levels of inflammation related molecules including IL-1β, IL-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD16, were increased after cisplatin treatment. Intraperitoneal (i.p.) or intrathecal (i.t.) injection with minocycline both alleviated cisplatin-induced mechanical allodynia and sensory deficits, and prevented IENFs loss. Furthermore, cisplatin enhanced triggering receptor expressed on myeloid cells 2 (TREM2) /DNAX-activating protein of 12 kDa (DAP12) signaling in the spinal cord microglia. The blockage of TREM2 by i.t. injecting anti-TREM2 neutralizing antibody significantly attenuated cisplatin-induced mechanical allodynia, sensory deficits and IENFs loss. Meanwhile, anti-TREM2 neutralizing antibody prominently suppressed the spinal IL-6, TNF-α, iNOS and CD16 mRNA level, but it dramatically up-regulated the anti-inflammatory cytokines IL-4 and IL-10. The data demonstrated that cisplatin triggered persistent activation of spinal cord microglia through strengthening TREM2/DAP12 signaling, which further resulted in CIPN. Functional blockage of TREM2 or inhibition of microglia both benefited for cisplatin-induced peripheral neuropathy. Microglial TREM2/DAP12 may serve as a potential target for CIPN intervention.

Topics: Adaptor Proteins, Signal Transducing; Animals; Astrocytes; Cisplatin; Cytokines; Disease Models, Animal; Hyperalgesia; Interleukin-10; Interleukin-1beta; Interleukin-4; Interleukin-6; Macrophage Activation; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Nitric Oxide Synthase Type II; Pain; Peripheral Nervous System Diseases; Receptors, IgG; Receptors, Immunologic; Signal Transduction; Spinal Cord; Tumor Necrosis Factor-alpha

In this study, we tested our working hypothesis that inhibiting the activation of microglia by systemic minocycline treatments can decrease the dosage of local tramadol injection in inflammatory pain. This study was therefore aimed to evaluate the actions of intraplantarly injected tramadol, intraperitoneally injected minocycline, or their combined treatments on the inflammation-induced hypernociception (thermal hyperalgesia, mechanical allodynia), edema, and pro- and anti-inflammatory cytokine levels of paw and spinal cord tissues in a rat model of carrageenan-induced hindpaw inflammation. While local tramadol or systemic minocycline caused a significant anti-hypernociceptive effect their combined treatments significantly enhanced anti-hypernociceptive action compared to each agent applied alone. Also anti-edematous actions of combined treatment were higher than that of their individual administrations. In addition, combined treatment significantly decreased the level of the pro-inflammatory cytokines and caused significant increases in anti-inflammatory cytokine level of paw and spinal cord tissues. The present finding can suggest that combined treatments of local tramadol and systemic minocycline may decrease the dose requirements for anti-hypernociceptive actions of local tramadol and this combination therapy might be a beneficial option for the inflammatory pain relief.

Topics: Animals; Carrageenan; Cytokines; Drug Therapy, Combination; Inflammation; Minocycline; Nociception; Pain; Rats; Tramadol

Infant nerve injury causes delayed adolescent neuropathic pain, but whether it also leads to psychiatric illness is unknown. Environmental enrichment (EE) increases social communication and activity. Thus, our goal was to test anxiety- and depression-like behaviors after infant peripheral nerve injury and evaluate the effect of environmental enrichment on these models of affective disorders.. Open field, elevated plus maze, sucrose preference, and pain behaviors (paw withdrawal threshold, spontaneous guarding score, and cold response to acetone) were measured in rats that received infant spared nerve injury (SNI). Enzyme-linked immune absorbent assay of cytokines was performed to evaluate the inflammatory response in the brain. Then, the ability of intracerebroventricular (ICV) injection of a microglia inhibitor, minocycline (MIN), and EE (a free-running wheel, a staircase, a plastic tunnel, a raised platform, and various colored balls) to reverse the infant SNI effects on behaviors and cytokines was examined.. Infant nerve injury resulted in adolescent anxiety- and depression-like behaviors. The medial prefrontal cortex, basolateral amygdala, and ventral hippocampus were skewed to a pro-inflammatory profile. ICV injection of MIN reduced anxiety- and depression-like behaviors without affecting pain behaviors. In addition, ICV MIN skewed the brain towards an anti-inflammatory profile. Finally, environmental enrichment improved anxiety- and depression-like behaviors, as well as pain behaviors. EE increased brain IL-10 and decreased IL-1β and TNF-α.. Infant nerve injury induces adolescent anxiety- and depression-like behaviors and central nervous inflammation. Environmental enrichment reduces these behaviors by normalizing the inflammation balance in the brain.

Topics: Age Factors; Animals; Animals, Newborn; Anti-Bacterial Agents; Anxiety; Brain; Cytokines; Depression; Disease Models, Animal; Environment; Exploratory Behavior; Injections, Intraventricular; Male; Maze Learning; Minocycline; Pain; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Sucrose

To unravel the underlying mechanism of minocycline in formalin-induced inflammatory pain, and to investigate the effects of minocycline on synaptic transmission in substantia gela-tinosa (SG) neurons of rat spinal dorsal horn.. Behavioral and immunohistochemistry experiments: 30 male Sprague-Dawley (SD) rats (3-5 weeks old) were randomly assigned to control (n=8 rats), model (n=8 rats), saline treatment model (n=6 rats) and minocycline treatment model (n=8 rats) groups. The control group was subcutaneously injected with normal saline on the right hindpaws. Acute inflammatory pain model was established by injecting 5% (volume fraction) formalin into the right hindpaws. The rats in the latter two groups received intraperitoneal injection of saline and minocycline 1 h before the formalin injection, respectively. The time of licking and lifting was recorded every 5 min within 1 h after the subcutaneous injection of normal saline or formalin for all the groups, which was continuously recorded for 1 h. One hour after the pain behavioral recording, the spinal cord tissue was removed following transcardial perfusion of 4% paraformaldehyde. The expression of c-Fos protein in spinal dorsal horn was observed by immunohistochemistry. Electrophysiological experiment: In vitro whole-cell patch-clamp recordings were performed in spinal cord parasagittal slices obtained from 26 male SD rats (3-5 weeks old). Two to five neurons were randomly selected from each rat for patch-clamp recording. the effects of minocycline, fluorocitrate and doxycycline on spontaneous excitatory postsynaptic currents (sEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs) of SG neurons were investigated.. Compared with the control group, both the licking and lifting time and the expression of c-Fos protein in ipsilateral spinal dorsal horn of the model group were significantly increased. Intraperitoneal injection of minocycline largely attenuated the second phase of formalin-induced pain responses (t=2.957, P<0.05). Moreover, c-Fos protein expression was also dramatically reduced in both the superficial lamina (I-II) and deep lamina (III-IV) of spinal dorsal horn (t. Minocycline can inhibit formalin-induced inflammatory pain and the expression of c-Fos protein in spinal dorsal horn. These effects are probably due to its enhancement in inhibitory synaptic transmission of SG neurons but not its effect on microglial activation or antibiotic action.

Topics: Animals; Anti-Bacterial Agents; Formaldehyde; Inflammation; Inhibitory Postsynaptic Potentials; Male; Minocycline; Pain; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine's potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.

Topics: Adverse Drug Reaction Reporting Systems; Analgesics; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Data Mining; Depression; Diclofenac; Drug Repositioning; Humans; Information Storage and Retrieval; Ketamine; Minocycline; Pain; United States; United States Food and Drug Administration

Topics: Analgesics; Animals; Formaldehyde; Male; Minocycline; Pain; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Synaptic Transmission

A 16-year-old boy developed left foot pain of unknown cause that was unresponsive to conservative treatment, associated with fever and difficulty walking. He was admitted to our hospital with osteomyelitis of the accessory and body of the navicular bone. Surgery could not be performed because the patient had been diagnosed with Wiskott-Aldrich syndrome. After antibiotic therapy, laboratory abnormalities and pain had resolved. One year after treatment, the patient had returned to his original level of sports activity. Both an accessory navicular and the body of the navicular bone may develop osteomyelitis in immunocompromised patients; early diagnosis is important for prescribing effective conservative treatment.

Topics: Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Clindamycin; Diagnosis, Differential; Foot; Foot Diseases; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Male; Minocycline; Osteomyelitis; Pain; Physical Therapy Modalities; Tarsal Bones; Treatment Outcome; Wiskott-Aldrich Syndrome

We examined the effect of repeated cold (RC) stress on cyclophosphamide (CPA)-induced cystitis/bladder pain in mice, in relation to macrophage activity. CPA, given i.p. at 400 mg/kg, caused bladder pain symptoms accompanying cystitis in both unstressed and RC-stressed mice, which were prevented by the macrophage inhibitor minocycline. A low dose, that is, 200 mg/kg, of CPA still produced bladder pain symptoms in unstressed but not RC-stressed mice. Lipopolysaccharide-induced cytokine production in peritoneal macrophages from RC-stressed mice was less than that from unstressed mice. Thus, RC stress appears to reduce CPA-induced bladder pain in mice, which may be associated with the decreased macrophage activity.

Topics: Animals; Cold Temperature; Cyclophosphamide; Cystitis; Cytokines; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Mice; Minocycline; Pain; Stress, Physiological; Urinary Bladder

Topics: Acne Vulgaris; Alkaptonuria; Anti-Bacterial Agents; Arthroscopy; Diagnosis, Differential; Humans; Hyperpigmentation; Knee Joint; Male; Middle Aged; Minocycline; Pain

Orthodontic tooth movement causes pain to a patient. Glial cells are nonneuronal cells in the central nervous system and are implicated in various types of pain. In this study, we assessed glial activation responses after experimental tooth movement using immunocytochemical detection of anti-CD11b (OX42) and glial fibrillary acidic protein immunoreactivity to illustrate the microglial and astrocytes response, respectively. In addition, the effect of minocycline in reducing pain during tooth movement was also investigated.. Fifty-five Sprague Dawley rats with and without administration of minocycline after 1, 3, 5, 7, and 14 days (n = 5, for each) of tooth movement were used. Immunohistochemistry for microglia (OX42) and astrocyte (glial fibrillary acidic protein) were performed at the medullary dorsal horn (trigeminal subnucleus caudalis). Three-dimensional quantitative analysis was performed with a confocal fluorescence microscope and a software program.. There was a significant increase in the OX42 and glial fibrillary acidic protein immunoreactivity in response to tooth movement in the medullary dorsal horn. Furthermore, systematic administration of minocycline, a selective inhibitor of microglial activation, significantly attenuated the nociceptive c-Fos expression in the medullary dorsal horn that was induced by experimental tooth movement.. These data indicate the possible importance of microglial activation in the development of orthodontic pain. This is also the first report on the systematic application of minocycline.

Topics: Animals; Astrocytes; Microglia; Minocycline; Pain; Rats, Sprague-Dawley; Tooth Movement Techniques

Physicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol-mediated-increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)-related traits would be seen.. "Drinking in the Dark" (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID-related pain responses and sensitivity was tested.. DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro-nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests.. Our results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex-specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro-nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex-specific differences in nociception.

Topics: Animals; Binge Drinking; Female; Hyperalgesia; Inflammation; Male; Mice; Minocycline; Pain; Sex Characteristics; Tigecycline

Stress has been shown to enhance pain sensitivity resulting in stress-induced hyperalgesia. However, the underlying mechanisms have yet to be elucidated. Using single-prolonged stress combined with Complete Freund's Adjuvant injection model, we explored the reciprocal regulatory relationship between neurons and microglia, which is critical for the maintenance of posttraumatic stress disorder (PTSD)-induced hyperalgesia. In our assay, significant mechanical allodynia was observed. Additionally, activated neurons in spinal dorsal horn were observed by analysis of Fos expression. And, microglia were also significantly activated with the presence of increased Iba-1 expression. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or minocycline (a specific microglia inhibitor) attenuated mechanical allodynia. Moreover, intrathecal administration of c-fos ASO significantly suppressed the activation of neurons and microglia. Interestingly, inhibition of microglia activation by minocycline significantly suppressed the activation of both neurons and microglia in spinal dorsal horn. P38 inhibitor SB203580 suppressed IL-6 production, and inhibition of IL-6 receptor (IL-6R) activation by tocilizumab suppressed Fos expression. Together, our data suggest that the presence of a "crosstalk" between activated microglia and neurons in the spinal dorsal horn, which might contribute to the stress-induced hyperactivated state, leading to an increased pain sensitivity.

Topics: Animals; Genes, fos; Hyperalgesia; Imidazoles; Interleukin-6; Male; Microglia; Minocycline; Neurons; Pain; Pain Threshold; Pyridines; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Dorsal Horn; Stress, Physiological

The aim of the present study was to investigate the role of the amygdala in the potentiative effect of minocycline, a semisynthetic tetracycline antibiotic, on morphine analgesia in male Wistar rats. We also examined the involvement of the amygdala μ-opioid and N-methyl-D-aspartate (NMDA) receptors in the minocycline-induced potentiation of morphine analgesia. Intraperitoneal administration of morphine (3-9 mg/kg) induced analgesia in a tail-flick test. Bilateral intra-amygdala injection of minocycline (10-20 μg/rat) enhanced the analgesic response of an ineffective dose of morphine (3 mg/kg). Injection of a higher dose of minocycline into the amygdala also induced analgesia. Moreover, bilateral intra-amygdala injection of naloxone (0.5-1.5 µg/rat) reversed minocycline-induced potentiation of morphine analgesia. Pretreatment of animals with NMDA (0.01-0.1 μg/rat, intra-amygdala) also inhibited the potentiative effect of minocycline on morphine response. Bilateral intra-amygdala injection of the same doses of naloxone or NMDA plus morphine had no effect on the tail-flick latency in the absence of minocycline. It can be concluded that the amygdala has a key role in the potentiative effect of minocycline on morphine analgesia. In addition, amygdala opioidergic and glutamatergic mechanisms may be involved, probably through μ-opioid and NMDA receptors, in the modulation of the minocycline-induced potentiation of morphine analgesia in the tail-flick test.

Topics: Amygdala; Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Hot Temperature; Injections, Intraperitoneal; Male; Minocycline; Morphine; N-Methylaspartate; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Random Allocation; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu

Peripheral inflammation induces central sensitization that displays the features by the development of pain hypersensitivity to the stimuli. It has been shown that activation of glia contributes to the development of behavioral hypersensitivity after peripheral inflammation. It has been suggested that Toll-like receptor 4 (TLR4) primarily expressed on microglia affects central pain response. The present study was designed to examine the expressions of TLR4 and microglia in the spinal cord in different time points of inflammatory pain induced by complete Freund's adjuvant (CFA). The results show that CFA induces significant pain hypersensitivity and paw edema as well as spinal dorsal horn (SDH) microglia activation with the increased expressions of OX-42 and TLR4 during the inflammatory pain, respectively. The quantification of TLR4 with Western Blot analysis also suggests the same patter with the morphological results during the progress of inflammatory pain. In addition, chronic minocycline hydrochloride intrathecal injection reverses pain hypersensitivity and suppresses activation of microglia and TLR4 induced by CFA, but has hardly any effects on paw edema. Taken together, our data demonstrate the importance of TLR4 and microglia in rats in CFA inflammatory pain states, and suggest that blockade of microglia should likely be considered as a therapeutic opportunity.

Topics: Animals; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Spinal; Male; Microglia; Minocycline; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Toll-Like Receptor 4; Up-Regulation

Damage on one side of the body can also result in pain on the contralateral unaffected side, called mirror-image pain (MIP). Currently, the mechanisms responsible for the development of MIP are unknown. In this study, we investigated the involvement of spinal microglia and interleukin-1β (IL-1β) in the development of MIP using a peripheral inflammatory pain model. After unilateral carrageenan injection, mechanical allodynia (MA) in both hind paws and the expression levels of spinal Iba-1, IL-1β, and GFAP were evaluated. Ipsilateral MA was induced beginning at 3 hours after carrageenan injection, whereas contralateral MA showed a delayed onset occurring 5 days after injection. A single intrathecal (i.t.) injection of minocycline, a tetracycline derivative that displays selective inhibition of microglial activation, or an interleukin-1 receptor antagonist (IL-1ra) on the day of carrageenan injection caused an early temporary induction of contralateral MA, whereas repeated i.t. treatment with these drugs from days 0 to 3 resulted in a long-lasting contralateral MA, which was evident in its advanced development. We further showed that IL-1β was localized to microglia and that minocycline inhibited the carrageenan-induced increases in spinal Iba-1 and IL-1β expression. Conversely, minocycline or IL-1ra pretreatment increased GFAP expression as compared with that of control rats. However, i.t. pretreatment with fluorocitrate, an astrocyte inhibitor, restored minocycline- or IL-1ra-induced contralateral MA. These results suggest that spinal IL-1β derived from activated microglia temporarily suppresses astrocyte activation, which can ultimately prevent the development of contralateral MA under inflammatory conditions. These findings imply that microglial IL-1β plays an important role in regulating the induction of inflammatory MIP.

Topics: Animals; Astrocytes; Carrageenan; Citrates; Disease Models, Animal; Functional Laterality; Gene Expression Regulation; Hyperalgesia; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Male; Microglia; Minocycline; Nerve Tissue Proteins; Pain; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1 Type I; Spinal Cord; Spinal Cord Dorsal Horn

The mechanisms associated with diabetes-induced neuropathic pain are complex and poorly understood. In order to understand the involvement of spinal microglia activity in diabetic pain, the present study investigated whether minocycline treatment is able to attenuate diabetic pain using a rat model. Diabetes was induced using a single intraperitoneal injection of streptozotocin (STZ). Minocycline was then intrathecally administered to the rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested weekly. The expression of OX-42, Iba-1, phospho-p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS), were examined in the spinal cord in order to evaluate the activation of microglia. The present study demonstrated that rats with STZ-induced diabetes exhibited increased mean plasma glucose concentration, decreased mean body weight and significant pain hypersensitivity compared with control rats. PWT and PWL values of rats with STZ-induced diabetes increased following treatment with minocycline. No differences were observed in expression levels of the microglial activity markers (OX-42, Iba-1 and phospho-p38 MAPK) between rats with STZ-induced diabetes and control rats. However, TNF-α, IL-1β and iNOS expression levels were higher in rats with STZ-induced diabetes compared with control rats. Following treatment with minocycline markers of microglial activation, including cytokines and iNOS, were downregulated in rats with STZ-induced diabetes. The results of the present study indicated that minocycline treatment may inhibit spinal microglial activation and attenuate diabetic pain in rats with STZ-induced diabetes.

Topics: Analgesics; Animals; Diabetes Mellitus, Experimental; Hyperalgesia; Inflammation Mediators; Interleukin-1beta; Male; Microglia; Minocycline; Nitric Oxide Synthase Type II; Pain; Rats, Sprague-Dawley; Spine; Tumor Necrosis Factor-alpha

Spinal root avulsion produces tactile and thermal hypersensitivity, neurodegeneration, and microglial and astrocyte activation in both the deafferented and the adjacent intact spinal cord segments. Following avulsion of the fifth lumbar spinal root, immediate and prolonged treatment with riluzole or minocycline for 2 weeks altered the development of behavioral hypersensitivity. Riluzole delayed the onset of thermal and tactile hypersensitivity and partially reversed established pain behavior. Minocycline effectively prevented and reversed both types of behavioral change. Histologic analysis revealed that both drugs reduced microglial staining in the spinal cord, with minocycline being more effective than riluzole. Astrocyte activation was ameliorated to a lesser extent. Surprisingly, neither drug provided a neuroprotective effect on avulsed motoneurons.. Immediate treatment of spinal root avulsion injuries with minocycline or riluzole prevents the onset of evoked pain hypersensitivity by reducing microglial cell activation. When treatment is delayed, minocycline, but not riluzole, reverses pre-established hypersensitivity. Thus, these drugs may provide a new translational treatment option for chronic avulsion injury pain.

Topics: Animals; Disease Models, Animal; Functional Laterality; Hyperalgesia; Male; Minocycline; Neurons; Neuroprotective Agents; Pain; Pain Threshold; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Riluzole; Spinal Cord Injuries; Spinal Nerve Roots; Time Factors

The research on sex differences in nociception and antinociception as well as sex and gender differences in pain and analgesia is a maturing field. There is a vast literature showing experimental and clinical pain suppressive effects induced by minocycline, especially in inflammatory pain. However, as far as we know, possible qualitative or quantitative sex differences in those effects remained to be examined. By employing the formalin test, which has two phases of experimental pain behavior that models nociceptive pain (i.e., first phase) and inflammatory pain (i.e., second phase), we initially evaluated the effect induced by minocycline in female or male C57BL/6 mice. The treatment reduced the second phase of licking behavior in both females and males, and the effects were quantitatively similar in both sexes. Likewise, the same sex-independent effect was observed in Swiss mice, suggesting a genotype-unspecific sex-independent effect. While minocycline is already being tested in clinical trials, this appears to be the first preclinical investigation of sex differences in the experimental pain suppressive effects induced by this widely studied drug. The independence of sex in the antinociceptive effect induced by minocycline may be hopefully translated to gender-independent analgesic effects, which would be surely promising in a therapeutic paradigm.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Female; Inflammation; Male; Mice; Mice, Inbred C57BL; Minocycline; Nociceptive Pain; Pain; Sex Factors; Species Specificity

Topics: Animals; Anti-Bacterial Agents; Bone Neoplasms; Brain-Derived Neurotrophic Factor; Female; Minocycline; Pain; Pain Threshold; Spinal Cord

It is well known that spinal glia plays a key role in the pathogenesis of pain. The present study was designed to determine the roles of spinal microglia in bee venom-induced persistent spontaneous nociception (PSN), mechanical hyperalgesia and inflammation. We determined the effects of microglia inhibitor minocycline on BV-induced PSN, mechanical hyperalgesia and inflammatory swelling. Pre-treatment with intrathecal administration of minocyline at different doses significantly inhibited BV-induced PSN and mechanical hyperalgesia, but had no effect on BV-induced inflammatory swelling. These data suggest that the activation of spinal microglia may play a key role in BV-induced nociception, but not inflammation.

Topics: Animals; Bee Venoms; Edema; Hyperalgesia; Inflammation; Injections, Spinal; Male; Microglia; Minocycline; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord; Touch

Previous studies have suggested that the release of brain-derived neurotrophic factor (BDNF) from microglia in spinal cord is necessary for maintaining pain hypersensitivity after nerve injury. However, little is known about its role in cancer-induced bone pain (CIBP), which is in some ways unique. This study demonstrates a critical role of minocycline (a potent inhibitor of microglial activation)-modulated BDNF in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP. We assessed mechanical threshold and spontaneous pain of CIBP rats. Moreover, minocycline was administered intrathecally from day 4 to day 6 (early stage) or from day 10 to day 12 (later stage), after carcinoma cell inoculation. Real-time PCR, Western blots, and double immunofluorescence were used to detect the expression of OX-42 (marker of activated microglia), phosphorylated p38-MAPK (p-p38), and BDNF. We found that intrathecal minocycline could prevent CIBP at an early stage of tumor growth (from day 4 to day 6). However, at the late stage (from day 10 to day 12), intrathecal minocycline had no effect. Moreover, the expression of OX-42 and BDNF under CIBP, peaking on day 6, were all reduced after minocycline injection from day 4 to day 6. The ability of minocycline-induced reduction of BDNF in the induction of behavioral hypersensitivity could provide an opportunity for alleviating CIBP.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Bone Neoplasms; Brain-Derived Neurotrophic Factor; Female; Hyperalgesia; Microglia; Minocycline; p38 Mitogen-Activated Protein Kinases; Pain; Pain Measurement; Pain Threshold; Phosphorylation; Rats; Rats, Sprague-Dawley; Spinal Cord

We previously demonstrated that intrathecal IL-1β caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL-1β-induced nociception in rats. The effects of minocycline (20 μg), fluorocitrate (1 nmol), and SB203580 (5 μg) on IL-1β (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen-activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL-1β activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P-p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6- and 2.7-fold, respectively) and 6 h (3.3- and 4.0-fold, respectively) following IL-1β injection, as compared with saline controls at 30 min (all P < 0.01). IL-1β induced P-p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL-1β-upregulated P-p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL-1β-induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL-1β-induced central sensitization and hyperalgesia in rats.

Topics: Animals; Citrates; Hyperalgesia; Injections, Spinal; Interleukin-1beta; Male; Minocycline; Pain; Pain Measurement; Rats; Rats, Wistar; Signal Transduction; Spinal Cord

Minocycline (Mino) and doxycycline (Dox) are second generation tetracyclines known to present several other effects, which are independent from their antimicrobial activities. We studied in a comparative way the anti-inflammatory effects of Mino and Dox, on acute models of peripheral inflammation in rodents (formalin test and peritonitis in mice, and carrageenan-induced paw oedema in rats). Immunohistochemical assays for TNF-alpha and iNOS in rat paws of carrageenan-induced oedema were also carried out as well as in vitro assays for myeloperoxidase (MPO) and lactate dehydrogenase (LDH). Furthermore, antioxidant activities were evaluated by the DPPH assay.. In the formalin test although Mino and Dox (1, 5, 10 and 25 mg/kg, i.p.) inhibited the first phase, they acted predominantly on the second phase of the test, where inhibition of the licking time close to 80% were observed. Mino and Dox were very efficacious in reducing the carrageenan-induced paw oedema in rats (10, 25 and 50 mg/kg, i.p.) and carrageenan-induced leucocyte migration (1 and 5 mg/kg, i.p.) to mice peritoneal cavities. Besides, they also significantly inhibited MPO and LDH releases at doses ranging from 0.001 to 1 μg/ml. Thus, in general, the anti-inflammatory activity of Dox was higher as compared to that of Mino, although the radical scavenging activity of Mino was of a magnitude 10 times higher.. Our data indicate that anti-inflammatory and antioxidant effects, involve the inhibition of iNOS and TNF-alpha, among other properties, and these encourage clinical studies of these compounds for new therapeutic applications, especially those were inflammation plays a role.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Carrageenan; Cell Movement; Doxycycline; Edema; Formaldehyde; Inflammation; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Minocycline; Neutrophils; Nitric Oxide Synthase Type II; Oxidation-Reduction; Pain; Pain Measurement; Peritonitis; Peroxidase; Picrates; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Painful neuropathy, a common complication of diabetes mellitus is characterized by allodynia and hyperalgesia. Recent studies emphasized on the role of non-neuronal cells, particularly microglia in the development of neuronal hypersensitivity. The purpose of the present study is to evaluate the effect of minocyline, a selective inhibitor of microglial activation to define the role of neuroimmune activation in experimental diabetic neuropathy. Cold allodynia and thermal and chemical hyperalgesia were assessed and the markers of inflammation and oxidative and nitrosative stress were estimated in streptozotocin-induced diabetic rats. Chronic administration of minocycline (40 and 80 mg/kg, i.p.) for 2 weeks started 2 weeks after diabetes induction attenuated the development of diabetic neuropathy as compared to diabetic control animals. In addition, minocyline treatment reduced the levels of interleukin-1β and tumor necrosis factor-α, lipid peroxidation, nitrite and also improved antioxidant defense in spinal cords of diabetic rats as compared to diabetic control animals. In contrast, minocycline (80 mg/kg, per se) had no effect on any of these behavioral and biochemical parameters assessed in age-matched control animals. The results of the present study strongly suggest that activated microglia are involved in the development of experimental diabetic neuropathy and minocycline exerted its effect probably by inhibition of neuroimmune activation of microglia. In addition, the beneficial effects of minocycline are partly mediated by its anti-inflammatory effect by reducing the levels of proinflammatory cytokines and in part by modulating oxidative and nitrosative stress in the spinal cord that might be involved in attenuating the development of behavioral hypersensitivity in diabetic rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Behavior, Animal; Biomarkers; Blood Glucose; Body Weight; Cold Temperature; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Formaldehyde; Hyperalgesia; Interleukin-1beta; Male; Minocycline; Oxidative Stress; Pain; Rats; Rats, Wistar; Reactive Nitrogen Species; Spinal Cord; Tumor Necrosis Factor-alpha

A role of neuropeptides in neuropathic pain development has been implicated; however, the neuroimmune interactions that are involved in the underlying mechanisms may be more important than previously thought. To examine a potential role of relations between glia cells and neuropeptides in neuropathic pain, we performed competitive reverse-transcription polymerase chain reaction (RT-PCR) from the dorsal lumbar spinal cord and the dorsal root ganglion (DRG) after chronic constriction injury (CCI) in the rat sciatic nerve. The RT-PCR results indicated that complement component 1, q subcomponent (C1q) mRNA expression was higher than glial fibrillary acidic protein (GFAP) in the spinal cord 3 and 7 days post-CCI, suggesting that spinal microglia and perivascular macrophages are more activated than astrocytes. In parallel, we observed a strong upregulation of prodynorphin mRNA in the spinal cord after CCI, with no changes in the expression of proenkephalin or pronociceptin. Conversely, the expression of GFAP mRNA in the DRG was higher than C1q, which suggests that the satellite cells are activated shortly after injury, followed by the macrophages and polymorphonuclear leukocytes infiltrating the DRG. In the DRG, we also observed a very strong upregulation of prodynorphin (1387%) as well as pronociceptin (122%) and a downregulation of proenkephalin (47%) mRNAs. Interestingly, preemptive and repeated i.p. injection of minocycline reversed the activation of microglia/macrophages in the spinal cord and the trafficking of peripheral immune cells into the DRG, and markedly diminished the upregulation of prodynorphin and pronociceptin in the DRG. We thus provide novel findings that inhibition of C1q-positive cells by minocycline can diminish injury-induced neuropeptide changes in the DRG. This suggests that immune cells-derived pronociceptive factors may influence opioid peptide expression. Therefore, the injury-induced activation of microglia and leukocytes and the subsequent activation of neuropeptides involved in nociception processes are potential targets for the attenuation of neuropathic pain.

Topics: Animals; Central Nervous System Agents; Disease Models, Animal; Enkephalins; Ganglia, Spinal; Lumbar Vertebrae; Male; Minocycline; Neuroimmunomodulation; Pain; Protein Precursors; Rats; Rats, Wistar; Receptors, Opioid; RNA, Messenger; Sciatic Neuropathy; Spinal Cord

In the present study, intraperitoneal administration of minocycline attenuated enhancing nociceptive behaviors in those rats receiving dual formalin injections (5% formalin followed at 7 days later by 1% formalin). The minocycline treatment did not prevent the increase in OX-42 and MHC class I labeling and morphological changes, but significantly attenuated upregulation of phospho-p38 in activated microglia. These results suggest that the later days of microglial activation with upregulated immune markers in the spinal cord contributes to enhancing long-term pain response by a pathway of p38 activation in microglia.

Topics: Animals; Antigens, CD1; Disease Models, Animal; Formaldehyde; Histocompatibility Antigens Class I; Male; Microglia; Minocycline; p38 Mitogen-Activated Protein Kinases; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors; Up-Regulation

We recently demonstrated that de novo lysophosphatidic acid (LPA) production in the spinal cord occurs in the early phase after nerve injury or LPA injection, and underlies the peripheral mechanisms of neuropathic pain. In this study, we examined the possible involvement of spinal cord microglia in such LPA-mediated functions. Intrathecal LPA injection rapidly increased the gene expression of CD11b and protein expression of phosphor-p38, accompanied by a morphological change of microglia from a ramified to amoeboid shape. Although early treatment with minocycline significantly inhibited LPA-induced neuropathic pain-like behavior and microglial activation, late treatment did not. Early treatment with minocycline also blocked LPA-evoked de novo LPA production and the increased activation of cytosolic phospholipase A(2), an LPA synthesis-related enzyme. Similar results were observed when the sciatic nerve was partially injured: early, but not late, treatment with minocycline significantly inhibited the injury-induced neuropathic pain, microglial activation, de novo LPA production and the underlying increased activation of cytosolic phospholipase A(2) as well as calcium-independent phospholipase A(2), another LPA synthesis-related enzyme. These findings suggest that the early phase of microglial activation is involved in de novo LPA production, and that this underlies the initial mechanisms of nerve injury-induced neuropathic pain.

Topics: Animals; Anti-Bacterial Agents; Blotting, Western; CD11b Antigen; Enzyme Activation; Immunohistochemistry; Injections, Spinal; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; p38 Mitogen-Activated Protein Kinases; Pain; Pain Measurement; Peripheral Nervous System Diseases; Phospholipases A2; Reverse Transcriptase Polymerase Chain Reaction; Sciatic Nerve

Few studies have evaluated the sclerosing efficacy of minocycline, and none have specifically compared its sclerosing efficacy and safety profiles with talc slurry in secondary spontaneous pneumothorax (SSP).. A retrospective analysis was conducted in patients with SSP who underwent chemical pleurodesis from January to December 2004 with minocycline or talc slurry in 12 public hospitals of Hong Kong.. There were 121 episodes of minocycline pleurodesis and 64 episodes of talc slurry pleurodesis. Immediate procedural failure were similar in the minocycline and talc slurry groups (21.5% vs. 28.1%, P = 0.31). Presence of interstitial lung disease, ≥ 2 previous episodes of pneumothorax, requiring mechanical ventilation during pleurodesis and persistent air leak before pleurodesis were independently associated with procedural failure. Pain was experienced in respectively 44.6% and 37.5% of the minocycline and the talc slurry groups. Pain was more common in patients receiving high doses of talc (≥ 5 g; P = 0.03). Respiratory distress was found in respectively 1.7% and 1.6% of the minocycline and talc slurry groups.. Minocycline and talc slurry had comparable sclerosing efficacy in SSP, with immediate success rates of >70%. Pain was the most common adverse effect and respiratory distress was uncommon. Both appeared to be effective and safe for chemical pleurodesis in SSP.

Topics: Aged; Chi-Square Distribution; China; Female; Hospitals, Public; Hospitals, University; Humans; Logistic Models; Male; Middle Aged; Minocycline; Odds Ratio; Pain; Pleurodesis; Pneumothorax; Respiration Disorders; Retrospective Studies; Risk Assessment; Risk Factors; Sclerosing Solutions; Secondary Prevention; Talc; Treatment Outcome

We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Blotting, Western; CD11b Antigen; CD11c Antigen; Dose-Response Relationship, Drug; Drug Tolerance; Glial Fibrillary Acidic Protein; Injections, Intraperitoneal; Male; Mice; Minocycline; Morphine; Neuroglia; Pain; Pain Measurement; Pain Threshold; Pentoxifylline; Platelet Aggregation Inhibitors; Sciatic Nerve; Sciatic Neuropathy; Spinal Cord

Loss of function is usually considered the major consequence of spinal cord injury (SCI). However, pain severely compromises the quality of life in nearly 70% of SCI patients. The principal aim of this study was to assess the contribution of Tumor necrosis factor alpha (TNF-alpha) to SCI pain. TNF-alpha blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain, especially following SCI. Following T13 spinal cord hemisection, we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept, a fusion protein blocker of TNF-alpha. Immediate treatment (starting at the time of injury) with etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after SCI. Delayed treatment had no effect. Immediate etanercept treatment also reduced spinal microglial activation assessed by OX-42 immunostaining, a putative marker of activated microglia. To assess whether the effects of etanercept were mediated via decreased microglial activation, we examined the effects of the microglial inhibitor, minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment. Minocycline also significantly reduced microglial OX-42 expression. Furthermore, minocycline decreased the expression of noxious-stimulation-induced c-Fos, suggesting an effect on evoked neuronal activity. This study demonstrates that TNF-alpha plays an important role in the establishment of neuropathic pain following SCI, seemingly dependent on microglial activation. Pharmacological targeting of TNF-alpha may offer therapeutic opportunities for treating SCI pain.

Topics: Animals; Anti-Bacterial Agents; Cell Count; Etanercept; Functional Laterality; Hot Temperature; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Injections, Spinal; Male; Microglia; Minocycline; Pain; Physical Stimulation; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor; Signal Transduction; Spinal Cord Injuries; Tumor Necrosis Factors

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Brain; Bronchodilator Agents; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraperitoneal; Male; Minocycline; Morphine; Naloxone; Opioid-Related Disorders; Oxycodone; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss

Spinal cord injury (SCI) results in the development of chronic pain syndromes that can persist indefinitely and cause reductions in quality of life. Treatment of chronic pain after SCI remains extremely challenging; thus, an important research goal is to determine whether early treatments can attenuate the subsequent development of pain conditions. The current study examined the hypothesis that early administration of the microglial-inhibiting drug minocycline could ameliorate the development of pain after SCI. Adult male Sprague-Dawley rats underwent SCI at the ninth thoracic spinal segment and received either vehicle or minocycline treatment for 5 days postinjury. Time course studies revealed that over 4 weeks post-SCI, microglial activation in vehicle-treated animals was progressively increased. Minocycline treatment resulted in reduction, but not prevention, of microglial activation over time. Electrophysiological experiments showed that early minocycline administration attenuated the development of chronic hyperresponsiveness of lumbar dorsal horn neurons. Similarly, behavioral assessment showed that minocycline also resulted in increased pain thresholds. These results suggest that inhibition of early neuroimmune events can have a powerful impact on the development of long-term pain phenomena following SCI and support the conclusion that modulation of microglial signaling may provide a new therapeutic strategy for patients suffering from post-SCI pain.

Topics: Action Potentials; Animals; Anti-Bacterial Agents; Behavior, Animal; Male; Microglia; Minocycline; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Sensory Receptor Cells; Spinal Cord Injuries

Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model.. Male Sprague-Dawley rats underwent either unilateral plantar hind paw incision (postoperative pain model) or L5 spinal nerve transection (neuropathic pain model), and the development of mechanical hypersensitivity was assessed using von Frey filaments. The microglial inhibitor minocycline was intraperitoneally administered daily for either 3 or 7 days. Spinal microglial activation was evaluated by OX42 immunohistochemistry. We also tested the effect of intrathecal administration of a p38 mitogen-activated protein kinase inhibitor, SB203580.. In the postoperative pain model, minocycline did not suppress mechanical hypersensitivity, but did inhibit an increase in spinal OX42 expression. In contrast, in the neuropathic pain model, minocycline reduced mechanical hypersensitivity in a dose-related manner and inhibited spinal OX42 expression. SB203580 attenuated hypersensitivity in the neuropathic pain model, but not in the postoperative pain model.. The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; CD11b Antigen; Enzyme Inhibitors; Fluorescent Antibody Technique; Hyperalgesia; Imidazoles; Immunohistochemistry; Male; Microglia; Minocycline; p38 Mitogen-Activated Protein Kinases; Pain; Pain, Postoperative; Peripheral Nervous System Diseases; Pyridines; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves

The present study investigated whether spinal astrocyte and microglia were activated in Buthus martensi Karch (BmK) venom-induced rat pain-related behaviors. The results showed that glial fibrillary acidic protein (GFAP) immunoreactivity indicative astrocyte activation in bilateral spinal cord started to increase by day 3, peaked at day 7 and gradually reversed at day 14 following intraplantar injection of BmK venom. Western blotting analysis confirmed GFAP expression was up-regulated by BmK venom. In contrast, bilateral spinal increase of OX-42 immunoreactivity indicative of microglial activation began at 4h peaked at day 1 and gradually reversed by days 3 to 7 after the administration of BmK venom. Pretreatment with either intrathecal injection of fluorocitrate or intraperitonial injection of minocycline, and two glial activation inhibitors, suppressed the spontaneous nociceptive responses, and prevented the primary thermal and bilateral mechanical hyperalgesia induced by BmK venom. The post-treatment with fluorocitrate or minocycline could not affect the mechanical hyperalgesia. Moreover, minocycline partially inhibited BmK venom-induced spinal c-Fos expression but lack of effects on BmK venom-induced paw edema. Taken together, the current study demonstrated that spinal astrocyte and microglial activation may contribute to BmK venom-induced rat pain-related behaviors. Thus, spinal glia may represent novel targets for effective treatment of pain syndrome associated with scorpion envenomation.

Topics: Analgesics, Non-Narcotic; Animals; Astrocytes; Behavior, Animal; Biomarkers; Citrates; Drug Administration Schedule; Edema; Glial Fibrillary Acidic Protein; Hyperalgesia; Macrophage-1 Antigen; Male; Microglia; Minocycline; Nociceptors; Organ Specificity; Pain; Pain Measurement; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Scorpion Stings; Scorpion Venoms; Scorpions; Spinal Cord; Time Factors

Experimental autoimmune neuritis (EAN) is a widely used animal model of the human acute inflammatory demyelinating polyradiculoneuropathy, which is the most common subtype of Guillain-Barré Syndrome. EAN is pathologically characterized by breakdown of the blood-nerve barrier, infiltration of reactive immune cells, local inflammation, demyelination in the peripheral nervous system and mechanical allodynia. Minocycline is known to have neuroprotective and anti-inflammatory effects. Furthermore, relieve of neuropathic pain following minocycline administration was observed in a variety of animal models. Here, we investigated the effects of minocycline on rat EAN. Suppressive treatment with minocycline (50 mg/kg body weight daily immediately after immunization) significantly attenuated the severity and duration of EAN. Macrophage and T-cell infiltration and demyelination in sciatic nerves of EAN rats treated with minocycline were significantly reduced compared to phosphate-buffered saline (PBS)-treated EAN rats. mRNA expressions of matrix metallopeptidase-9, inducible nitric oxide synthase and pro-inflammatory cytokines interleukin-1 beta and tumour necrosis factor-alpha in EAN sciatic nerves were greatly decreased by administration of minocycline as well. Furthermore, minocycline attenuated mechanical allodynia in EAN rats and greatly suppressed spinal microglial activation. All together, our data showed that minocycline could effectively suppress the peripheral and spinal inflammation (immune activation) to improve outcome in EAN rats, which suggests that minocycline may be considered as a potential candidate of pharmacological treatment for autoimmune-mediated neuropathies.

Topics: Animals; Anti-Bacterial Agents; Body Weight; Disease Models, Animal; Guillain-Barre Syndrome; Humans; Inflammation; Lymphocytes; Male; Matrix Metalloproteinase 9; Minocycline; Monocytes; Neuritis, Autoimmune, Experimental; Pain; Rats; Sciatic Nerve

Many in vitro and fewer in vivo studies have shown that tetracyclines present anti-inflammatory activity. We investigated if a novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline, 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), also induced antinociceptive and anti-inflammatory effects.. Antibacterial effects against a minocycline-sensitive Staphylococcus aureus strain were evaluated by applying a cylinder-plate agar diffusion technique. Antibacterial effects of diluted serum from mice pre-treated with minocycline or PMIN were also evaluated. Ca2+ binding activity was assessed by spectrophotometry. Formalin-induced nociceptive responses and carrageenan-induced paw oedema were evaluated in mice. The rota-rod apparatus was used to evaluate motor coordination.. Minocycline, but not PMIN, inhibited bacterial growth. Serum from mice treated with minocycline, but not with PMIN, also induced such an effect. The UV absorption spectrum of solutions of minocycline, but not those of PMIN, was markedly changed in the presence of Ca2+. Minocycline or PMIN inhibited both phases of formalin-induced nociception and carrageenan-induced paw oedema. It is unlikely that antinociception resulted from lack of motor coordination, as tetracycline did not impair the performance of mice on the rotating rod.. These results indicate that inhibition of nociception and oedema by tetracyclines is neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the treatment of painful and inflammatory diseases, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Cations, Divalent; Chelating Agents; Edema; Male; Mice; Microbial Sensitivity Tests; Minocycline; Molecular Structure; Motor Activity; Pain; Pain Measurement; Pyrazoles; Rotarod Performance Test; Staphylococcus aureus

Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here, we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force, and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation.

Topics: Analgesia; Analysis of Variance; Animals; Cell Line; Cells, Cultured; Conditioning, Operant; Cyclooxygenase 1; Dose-Response Relationship, Drug; Drug Interactions; Male; Microglia; Minocycline; Morphine; Narcotics; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; Reward; RNA, Messenger; Spatial Behavior

Glia, particularly astrocytes and microglia, are known to play an important role in central sensitization and are strongly implicated in the exaggerated pain states. In the present study, we determined the effect of minocycline, an inhibitor of microglial activation, in acute nociception, peritonitis, and the development and maintenance of hypersensitivity following chronic constriction injury of the sciatic nerve in rats. A single dose of minocycline (30 or 100 mg/kg, i.p.) 30 min before acetic acid or zymosan injection did not attenuate the nociceptive behavior in mice. It had no effect on the early events of peritoneal inflammation (vascular permeability, inflammatory cell infiltration, and release of pro-inflammatory cytokines) in acetic acid or zymosan-injected mice. In addition, minocycline (30 or 100 mg/kg, i.p.) did not alter basal nociceptive responses in the tail immersion test. Chronic administration of minocycline (10 or 30 mg/kg, i.p.) for 7 days started before nerve injury significantly prevented the development of neuropathic pain, interestingly, it further delayed the development of hypersensitivity. In contrast, single injection of minocycline failed to reverse hypersensitivity when administered during the development of neuropathic pain. No significant effects were observed on hypersensitivity when treatment was started once neuropathic state was established. Pre-treatment, but not post-treatment, with minocycline markedly attenuated increased pro-inflammatory cytokines release and oxidative and nitrosative stress in mononeuropathic rats. These results suggest that minocycline had no effect on acute peritoneal inflammation, nociception, and chronic administration of minocycline when started early before peripheral nerve injury could attenuate and further delays the development of neuropathic pain. Concluding, this study clearly shows minocycline, an inhibitor of microglial activation, by inhibiting the release of pro-inflammatory mediators and reducing oxidative stress prevented the development of neuropathic pain.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Drug Administration Schedule; Inflammation Mediators; Injections, Intraperitoneal; Male; Mice; Microglia; Minocycline; Oxidative Stress; Pain; Pain Measurement; Peritonitis; Rats; Rats, Wistar; Sciatic Neuropathy

Recent research has shown that microglial cells which are strongly activated in neuropathy can influence development of allodynia and hyperalgesia. Here we demonstrated that preemptive and repeated i.p., administration (16 h and 1 h before injury and then after nerve ligation twice daily for 7 days) of minocycline (15; 30; 50 mg/kg), a potent inhibitor of microglial activation, significantly attenuated the allodynia (von Frey test) and hyperalgesia (cold plate test) measured on day 3, 5, 7 after chronic constriction injury (CCI) in rats. Moreover, the 40% improvement of motor function was observed. In mice, i.p., administration of minocycline (30 mg/kg) or pentoxifylline (20 mg/kg) according to the same schedule also significantly decreased allodynia and hyperalgesia on day 7 after CCI. Antiallodynic and antihyperalgesic effect of morphine (10 mg/kg; i.p.) was significantly potentiated in groups preemptively and repeatedly injected with minocycline (von Frey test, 18 g versus 22 g; cold plate test, 13 s versus 20 s in rats and 1.2 g versus 2.2 g; 7.5 s versus 10 s in mice; respectively) or pentoxifylline (1.3 g versus 3 g; 7.6 s versus 15 s in mice; respectively). Antiallodynic and antihyperalgesic effect of morphine (30 microg; i.t.) given by lumbar puncture in mice was also significantly potentiated in minocycline-treated group (1.2 g versus 2.2 g; 7.5 s versus 11 s; respectively). These findings indicate that preemptive and repeated administration of glial inhibitors suppresses development of allodynia and hyperalgesia and potentiates effects of morphine in rat and mouse models of neuropathic pain.

Topics: Animals; Disease Models, Animal; Drug Synergism; Hyperalgesia; Male; Mice; Minocycline; Morphine; Neuralgia; Neuroglia; Pain; Pentoxifylline; Rats; Rats, Wistar

Several lines of evidence suggest that extracellular ATP plays a role in pain signaling through the activation of ionotropic P2X-receptors, especially homomeric P2X3- and heteromeric P2X2/3-receptors on capsaicin-sensitive and -insensitive primary afferent neurons, respectively, at peripheral and spinal sites. We investigated the mechanisms of the induction and maintenance of mechanical allodynia produced by a single intrathecal (i.t.) administration of ATP in rats. We found that i.t. administration of ATP and the P2X-receptor agonist alpha,beta-methylene-ATP produced tactile allodynia which lasted more than 1 week. The i.t. ATP- and alpha,beta-methylene-ATP-produced long-lasting allodynia remained in neonatal capsaicin-treated adult rats. I.t. administration of a P2X3/P2X2/3-receptor selective antagonist completely prevented the induction (co-administration on day 0) and partially attenuated the early phase (day 1 post-ATP administration), but not the late phase (day 7 post-ATP administration) of maintenance of allodynia. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely prevented the induction phase, but not the early and late phases of maintenance of allodynia. Immunohistochemical and immunoblotting studies for microglial and astrocytic markers revealed that i.t. ATP administration caused spinal microglial activation within 1 day, and astrocytic activation which peaked at 1-3 days after ATP administration. Furthermore, minocycline, a microglial inhibitor, attenuated the induction but not the early and late phases of maintenance, while fluorocitrate, a glial metabolic inhibitor, attenuated the induction and the early phase but not the late phase of maintenance. Taken together, these results suggest that the activation of P2X-receptors, most likely spinal P2X2/3-receptors on capsaicin-insensitive primary afferent neurons, triggers the induction of long-lasting allodynia through NMDA receptors, and the induction and early maintenance phase, but not the late phase, is mediated through the functions of spinal glial cells.

Topics: Adenosine Triphosphate; Animals; Astrocytes; Behavior, Animal; Blotting, Western; Capsaicin; Citrates; Immunohistochemistry; Injections, Spinal; Ligation; Male; Microglia; Minocycline; Neuroglia; Pain; Pain Measurement; Phenols; Physical Stimulation; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Purinergic P2; Receptors, Purinergic P2X2; Sciatic Nerve; Spinal Cord

Tetracyclines induce anti-inflammatory effects unrelated to their antimicrobial activities. We investigated the effect induced by minocycline and doxycycline in models of nociceptive and inflammatory pain, edema, fever, cell migration and formation of fibrovascular tissue, as these effects have not been fully investigated. Tetracyclines were administered via intraperitoneal route 1 h before the tests. Minocycline and doxycycline (100 mg/kg) inhibited the second phase of the formalin-induced nociceptive response in mice. Doxycycline (100 mg/kg) also inhibited the first phase. The nociceptive response induced by phorbol 12,13-didecanoate (PDD) in mice was inhibited by doxycycline (100 mg/kg). Furthermore, carrageenan-induced mechanical allodynia in rats was inhibited by doxycycline and minocycline (50 or 100 mg/kg). However, they did not enhance the latency in the hot-plate test. It is unlikely that antinociception resulted from motor incoordination or muscle relaxing effect, as both tetracyclines (100 mg/kg) did not impair the motor activity of mice in the rota-rod test. Doxycycline (50 or 100 mg/kg) or minocycline (50 or 100 mg/kg) inhibited carrageenan-induced paw edema in rats. However, only minocycline (100 mg/kg) inhibited PDD-induced edema. Carrageenan-induced leukocyte migration into the peritoneal cavity of rats was inhibited by both tetracyclines (100 mg/kg). Endotoxin-induced fever in rats was also inhibited by doxycycline (50 or 100 mg/kg) or minocycline (100 mg/kg). Finally, formation of fibrovascular tissue induced by subcutaneous implant of a cotton pellet in mice was inhibited by a 6-day administration of both tetracyclines (50 or 100 mg/kg day). Concluding, this study clearly shows the antinociceptive and anti-inflammatory activities of these second-generation tetracyclines.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Carrageenan; Doxycycline; Edema; Fever; Formaldehyde; Hot Temperature; Lipopolysaccharides; Male; Mice; Minocycline; Motor Activity; Pain; Phorbol Esters; Rats; Rats, Wistar

It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Edema; Electrophysiology; Formaldehyde; Genes, fos; Hindlimb; Inflammation; Injections, Intraperitoneal; Male; Minocycline; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord

Traumatic spinal cord injury (SCI) results not only in motor impairment but also in chronic central pain, which can be refractory to conventional treatment approaches. It has been shown recently that in models of peripheral nerve injury, spinal cord microglia can become activated and contribute to development of pain. Considering their role in pain after peripheral injury, and because microglia are known to become activated after SCI, we tested the hypothesis that activated microglia contribute to chronic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal cord contusion injury. Four weeks after injury, when lumbar dorsal horn multireceptive neurons became hyperresponsive and when behavioral nociceptive thresholds were decreased to both mechanical and thermal stimuli, intrathecal infusions of the microglial inhibitor minocycline were initiated. Electrophysiological experiments showed that minocycline rapidly attenuated hyperresponsiveness of lumbar dorsal horn neurons. Behavioral data showed that minocycline restored nociceptive thresholds, at which time spinal microglial cells assumed a quiescent morphological phenotype. Levels of phosphorylated-p38 were decreased in SCI animals receiving minocycline. Cessation of delivery of minocycline resulted in an immediate return of pain-related phenomena. These results suggest an important role for activated microglia in the maintenance of chronic central below-level pain after SCI and support the newly emerging role of non-neuronal immune cells as a contributing factor in post-SCI pain.

Topics: Animals; Chronic Disease; Male; Microglia; Minocycline; Motor Activity; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Thoracic Vertebrae

Fractalkine (FKN) evokes nociceptive behavior in nai ve rats, whereas minocycline attenuates pain acutely after neuronal injury. We show that, in nai ve rats, FKN causes hyperresponsiveness of lumbar wide dynamic range neurons to brush, pressure and pinch applied to the hindpaw. One day after spinal nerve ligation (SNL), minocycline attenuates after-discharge and responses to brush and pressure. In contrast, minocycline does not alter evoked neuronal responses 10 days after SNL or sciatic constriction, but increases spontaneous discharge. We speculate that microglia rapidly alter sensory neuronal activity in nai ve and neuropathic rats acutely, but not chronically, after injury.

Topics: Action Potentials; Animals; Chemokine CX3CL1; Chemokines, CX3C; Ligation; Male; Membrane Proteins; Minocycline; Pain; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Spinal Nerves

Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Blotting, Western; Cells, Cultured; Immunohistochemistry; Inflammation; Injections, Spinal; Lipopolysaccharides; Male; Microglia; Minocycline; p38 Mitogen-Activated Protein Kinases; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Spinal Cord

Fractalkine is a chemokine that is tethered to the extracellular surface of neurons. Fractalkine can be released, forming a diffusible signal. Spinal fractalkine (CX3CL1) is expressed by sensory afferents and intrinsic neurons, whereas its receptor (CX3CR1) is predominantly expressed by microglia. Pain enhancement occurs in response both to intrathecally administered fractalkine and to spinal fractalkine endogenously released by peripheral neuropathy. The present experiments examine whether fractalkine-induced pain enhancement is altered by a microglial inhibitor (minocycline) and/or by antagonists/inhibitors of three putative glial products implicated in pain enhancement: interleukin-1 (IL1), interleukin-6 (IL6) and nitric oxide (NO). In addition, it extends a prior study that demonstrated that intrathecal fractalkine-induced mechanical allodynia is blocked by a neutralizing antibody to the rat fractalkine receptor, CX3CR1. Here, intrathecal anti-CX3CR1 also blocked fractalkine-induced thermal hyperalgesia. Furthermore, blockade of microglial activation with minocycline prevented both fractalkine-induced mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). Microglial activation appears to lead to the release of IL1, given that pretreatment with IL1 receptor antagonist blocked both fractalkine-induced mechanical allodynia and thermal hyperalgesia. IL1 is not the only proinflammatory cytokine implicated, as a neutralizing antibody to rat IL6 also blocked fractalkine-induced pain facilitation. Lastly, NO appears to be importantly involved, as l-NAME, a broad-spectrum NO synthase inhibitor, also blocked fractalkine-induced effects. Taken together, these data support that neuronally released fractalkine enhances pain via activation of spinal cord glia. Thus, fractalkine may be a neuron-to-glia signal triggering pain facilitation.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Blocking; Chemokine CX3CL1; Chemokines, CX3C; Enzyme Inhibitors; Hot Temperature; Hyperalgesia; Injections, Spinal; Interleukin-6; Male; Membrane Proteins; Microglia; Microinjections; Minocycline; NG-Nitroarginine Methyl Ester; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord

Microglia, the intrinsic macrophages of the central nervous system, have previously been shown to be activated in the spinal cord in several rat mononeuropathy models. Activation of microglia and subsequent release of proinflammatory cytokines are known to play a role in inducing a behavioral hypersensitive state (hyperalgesia and allodynia) in these animals. The present study was undertaken to determine whether minocycline, an inhibitor of microglial activation, could attenuate both the development and existing mechanical allodynia and hyperalgesia in an L5 spinal nerve transection model of neuropathic pain. In a preventive paradigm (to study the effect on the development of hypersensitive behaviors), minocycline (10, 20, or 40 mg/kg intraperitoneally) was administered daily, beginning 1 h before nerve transection. This regimen produced a decrease in mechanical hyperalgesia and allodynia, with a maximum inhibitory effect observed at the dose of 20 and 40 mg/kg. The attenuation of the development of hyperalgesia and allodynia by minocycline was associated with an inhibitory action on microglial activation and suppression of proinflammatory cytokines at the L5 lumbar spinal cord of the nerveinjured animals. The effect of minocycline on existing allodynia was examined after its intraperitoneal administration initiated on day 5 post-L5 nerve transection. Although the postinjury administration of minocycline significantly inhibited microglial activation in neuropathic rats, it failed to attenuate existing hyperalgesia and allodynia. These data demonstrate that inhibition of microglial activation attenuated the development of behavioral hypersensitivity in a rat model of neuropathic pain but had no effect on the treatment of existing mechanical allodynia and hyperalgesia.

Topics: Animals; Cytokines; Gene Expression; Hyperalgesia; Hypersensitivity; Microglia; Minocycline; Pain; Rats; Rats, Sprague-Dawley; Spinal Nerves

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Fever; Hemoptysis; Hemorrhage; Humans; Kidney; Leg; Leptospirosis; Liver; Lung Diseases; Male; Minocycline; Muscle, Skeletal; Pain; Radiography, Thoracic; Respiratory Distress Syndrome; Tomography, X-Ray Computed

To determine the comparability of a text to a mannequin format for the assessment of joint counts (JC) among patients with rheumatoid arthritis (RA) participating in a randomized clinical trial (RCT).. A subgroup of patients participating in the MIRA (Minocycline in RA) RCT completed self-administered JC and joint scores (JS), which were compared to those of a trained assessor.. JC and JS data were consistently higher for the patient than for the assessor. Higher correlations were obtained for JC than for JS.. Our data suggest JC can be used in the context of clinical trials or in the clinical setting, but are not interchangeable with trained assessor JC.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Female; Humans; Male; Manikins; Middle Aged; Minocycline; Pain; Randomized Controlled Trials as Topic; Self-Examination

To report changes in the white blood cell (WBC) counts in expressed prostatic secretions (EPS) in men with pelvic symptoms undergoing thrice-weekly prostatic massage combined with antimicrobial therapy.. The study comprised a retrospective analysis of the records of 35 patients (mean age 45.3 years, range 28-70, SD, 12.03) with pelvic pain, pain in the lower back, obstructive urinary symptoms, irritative urinary symptoms, or sexual dysfunction, who had undergone the same diagnosis and treatment protocol in a genitourinary clinic in Manila, Philippines, from September 1992 to September 1995.. EPS were obtained 347 times in 35 patients (median 9 times per patient, range 6-16). In 26 of the 35 (74%) patients the WBC count in the EPS was < 10 per oil-immersion field (OIF, x1000) at the first prostatic massage. In 34 of 35 (97%) patients the WBC count rose to > or = 10 as prostatic massage continued on a thrice-weekly schedule. The mean (range, SD) initial WBC count in the EPS was 8.4 (1-48, 8.43) and the maximum was 40.9 (6-60, 19.05); the difference between these values was 32.5 (3-57, 18.78; 95% confidence interval 26.1-40.1) and the difference was statistically significant (paired t-test, P < 0.001).. The classification of patients into those with prostatodynia or prostatitis based on one EPS examination is misleading and thrice-weekly massage of the prostate is better than a single collection of EPS to obtain the most purulent sample for Gram staining and culture.

Topics: Adult; Aged; Anti-Infective Agents, Urinary; Antibiotics, Antineoplastic; Bacterial Infections; Drug Therapy, Combination; Humans; Leukocyte Count; Low Back Pain; Male; Massage; Middle Aged; Minocycline; Ofloxacin; Pain; Pelvic Pain; Prostatitis; Retrospective Studies; Sexual Dysfunction, Physiological; Urinary Retention

Ureaplasma urealyticum has been considered to be a pathogen of nongonococcal urethritis. To elucidate the pathogenicity of this microorganism in chronic prostatitis, U. urealyticum was isolated from patients with chronic prostatitis and prostatodynia. Using the Taylor-Robinson's method, U. urealyticum was detected in expressed prostatic secretion (EPS) or urine voided after prostatic massage (VB3) in 40 (41.2%) out of 97 patients with chronic prostatitis and 6 (20.0%) out of 30 patients with prostatodynia. Seventeen patients with U. urealyticum-positive chronic prostatitis, 13 of whom had failed to respond to the treatment by other antimicrobial agents, were treated with minocycline. In 16 (94.1%) of the 17 patients, U. urealyticum was eradicated and in 14 patients (82.4%), the elevated white blood cell count was markedly lowered in EPS or VB3. U. urealyticum may prove to be an etiological microorganism of chronic prostatitis.

Topics: Chronic Disease; Humans; Male; Minocycline; Pain; Prostatic Diseases; Prostatitis; Ureaplasma