Inflammatory Pain Model Research Articles

Pyrazolo-Pyrimidinones with Improved Solubility and Selective Inhibition of Adenylyl Cyclase Type 1 Activity for Treatment of Inflammatory Pain.

Adenylyl cyclase isoform 1 (AC1) is considered a promising target for treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone scaffold as potent and selective inhibitors of Ca2+/CaM-mediated AC1 activity; however, the molecules suffered from poor aqueous solubility. The current study presents a strategy to improve aqueous solubility of the scaffold by reduction of crystal packing energy and increasing rotational degrees of freedom within the molecule. Structure-activity and property relationship studies identified the second generation lead 7-47A (AC10142A) that demonstrated and AC1 IC50 value of 0.26 μM and aqueous solubility of 74 ± 7 μM. After in vitro ADME characterization, the scaffold advanced to in vivo pharmacokinetic evaluation, demonstrating adequate levels of exposure. Finally, 7-47A exhibited antiallodynic efficacy in a rat complete Freund's adjuvant model for inflammatory pain showing improvement over previous iterations of this scaffold. These results further validate AC1 inhibition as a viable therapeutic strategy for treating chronic and inflammatory pain.

A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.

Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments. An opioid tolerance model was developed in male C57BL/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5 days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch-clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments. VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice. NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.

Slack potassium channels in spinal dorsal horn neurons control neuropathic pain and acute itch.

The sodium-activated potassium channel Slack (KNa1.1, Kcnt1) plays a critical role in tuning neuronal excitability. Previous studies have revealed that Slack is expressed in neurons of the superficial dorsal horn of the spinal cord. However, the precise role of Slack in spinal dorsal horn neurons is unclear. In this study, we used mice in which Slack is conditionally ablated in spinal dorsal horn neurons (Lbx1-Slack-/- mice) and analyzed their behaviors in various models of pain and itch. Lbx1-Slack-/- mice exhibited increased neuropathic pain behavior after peripheral nerve injury but normal responses in a model of inflammatory pain. Unexpectedly, Lbx1-Slack-/- mice demonstrated increased scratching after intradermal injection of chloroquine, LY344864, and histamine. Moreover, neuromedin B receptors are coexpressed with Slack in the dorsal horn, and scratching after intrathecal delivery of neuromedin B was increased in Lbx1-Slack-/- mice. Our study provides in vivo evidence that Slack expressed in spinal dorsal horn neurons inhibits nerve injury-induced allodynia and acute itch induced by various pruritogens.

Investigation of the anti-inflammatory, anti-pruritic, and analgesic effects of sophocarpine inhibiting TRP channels in a mouse model of inflammatory itch and pain

Ethnopharmacological relevanceSophocarpine is a bioactive compound extracted from the dried root of Sophorae Flavesentis Aiton, a plant that has been used for thousands of years for various conditions including skin itch and pain. Its antipruritic and analgesic effects are suggested in publications, while the molecular mechanisms underneath interacting with TRP channels are not understood. Aim of the studyWe investigated the anti-inflammatory, antipruritic, and analgesic effects of sophocarpine in a murine inflammatory itch and pain model to elucidate the underlying mechanisms. Materials and methodsWe evaluated sophocarpine's anti-pruritic and analgesic effects by monitoring mice's scratching and wiping behaviors, and the anti-inflammatory effect by measuring psoriasis area and severity index (PASI) score. The mRNA and protein expression of TRPA1/TRPV1 was analyzed by real-time quantitative polymerase chain reaction and western blotting. We further investigated the relationship between sophocarpine and TRPA1/TRPV1 in mice administered allyl-isothiocyanate (AITC) or capsaicin and by molecular docking. ResultsWe found that sophocarpine decreased scratching bouts, wipes, and the PASI score, reduced the TNF-α and IL-1β in the skin and TRPA1 and TRPV1 in the trigeminal ganglion. Pretreatment of sophocarpine decreased AITC-induced scratching bouts and wipes and capsaicin-induced wipes. We also found potential competitive bindings between sophocarpine and AITC/capsaicin to TRPA1/TRPV1. ConclusionsSophocarpine is a potential competitive inhibitor of TRPA1 and TRPV1 channels eliciting strong anti-inflammatory, anti-pruritic, and analgesic effects, suggesting its significant therapeutic potential in treating diseases with inflammatory itch and pain.

Benzylpiperidine derivatives as new dual μ-opioid and σ1 receptor ligands with potent antinociceptive effects

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ1R) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σ1R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ1R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [Ki (MOR) = 56.4 nM] and σ1R [Ki (σ1R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED50 = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED50 = 6.88 mg/kg in mice), formalin test (ED50 = 13.98 mg/kg in rats) and complete Freund’s adjuvant (CFA)-induced chronic pain model (ED50 = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.

Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models.

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.

Ruscogenin Exerts Anxiolytic-Like Effect via Microglial NF-κB/MAPKs/NLRP3 Signaling Pathways in Mouse Model of Chronic Inflammatory Pain.

Long-term inflammation can cause chronic pain and trigger patients' anxiety by sensitizing the central nervous system. However, effective drugs with few side effects for treating chronic pain-induced anxiety are still lacking. The anxiolytic and anti-inflammatory effects of ruscogenin (RUS), an important active compound in Ophiopogon japonicus, were evaluated in a mouse model of chronic inflammatory pain and N9 cells. RUS (5, 10, or 20 mg/kg/day, i.g.) was administered once daily for 7 days after CFA injection; pain- and anxiety-like behaviors were assessed in mice. Anti-inflammatory effect of RUS (0.1, 1, 10 μM) on N9 microglia after LPS treatment was evaluated. Inflammatory markers (TNF-α, IL-1β, IL-6, CD86, IL-4, ARG-1, and CD206) were measured using qPCR. The levels of IBA1, ROS, NF-κB, TLR4, P-IKK, P-IκBα, and P65, MAPKs (ERK, JNK, and P38), NLRP3 (caspase-1, ASC, and NLRP3) were detected by Western blotting or immunofluorescence staining. The potential target of RUS was validated by molecular docking and adeno-associated virus injection. Mice in CFA group exhibited allodynia and anxiety-like behaviors. LPS induced neuroinflammation in N9 cells. Both CFA and LPS increased the levels of IBA1, ROS, and inflammatory markers. RUS (10 mg/kg invivo and 1 μM invitro) alleviated these alterations through NF-κB/MAPKs/NLRP3 signaling pathways but had no effect on pain hypersensitivity. TLR4 strongly interacted with RUS, and TLR4 overexpression abolished the effects of RUS on anxiety and neuroinflammation. RUS exerts anti-inflammatory and anxiolytic effects via TLR4-mediated NF-κB/MAPKs/NLRP3 signaling pathways, which provides a basis for the treatment of chronic pain-induced anxiety.

Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.

The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom-derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX-III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore-guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1-SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1-SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off-target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7-specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications.

Intrathecal administration of MCRT produced potent antinociception in chronic inflammatory pain models via μ-δ heterodimer with limited side effects

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the μ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.

Analgesic Effect of Human Placenta Hydrolysate on CFA-Induced Inflammatory Pain in Mice.

To evaluate the efficacy of human placenta hydrolysate (HPH) in a mice model of CFA-induced inflammatory pain. TNF-α, IL-1β, and IL-6 are key pro-inflammatory cytokine factors for relieving inflammatory pain. Therefore, this study investigates whether HPH suppresses CFA-induced pain and attenuates the inflammatory process by regulating cytokines. In addition, the relationship between neuropathic pain and HPH was established by staining GFAP and Iba-1 in mice spinal cord tissues. This study was conducted for a total of day 28, and inflammatory pain was induced in mice by injecting CFA into the right paw at day 0 and day 14, respectively. 100 μL of 20% glucose and polydeoxyribonucleotide (PDRN) and 100, 200, and 300 μL of HPH were administered intraperitoneally twice a week. In the CFA-induced group, cold and mechanical allodynia and pro-inflammatory cytokine factors in the spinal cord and plantar tissue were significantly increased. The five groups of drugs evenly reduced pain and gene expression of inflammatory factors, and particularly excellent effects were confirmed in the HPH 200 and 300 groups. Meanwhile, the expression of GFAP and Iba-1 in the spinal cord was increased by CFA administration but decreased by HPH administration, which was confirmed to suppress damage to peripheral ganglia. The present study suggests that HPH attenuates CFA-induced inflammatory pain through inhibition of pro-inflammatory cytokine factors and protection of peripheral nerves.

Monnieriside A from Evolvulus linarioides promotes antinociceptive effects in models of inflammatory and postoperative pain in male mice

Monnieriside A (MoA) is a chromone isolated from Evolvulus linarioides. This study investigated the antinociceptive potential of MoA in mice. MoA (0.01–100 mg/kg, i.p.) inhibited nociception in the inflammatory phase of the formalin test without causing motor impairment. MoA (0.1–100 mg/kg, i.p.) also reduced hindpaw mechanical allodynia caused by either intraplantar injection of Complete Freund’s Adjuvant (CFA) or surgical paw incision to simulate postoperative pain. Postoperative antinociception was accompanied by reduced IL-1β levels in the incised paw, assessed by ELISA. The antinociceptive action of MoA (100 mg/kg, i.p.) was preserved in IL-10 knockout mice submitted to paw incision, indicating that IL-10 is not essential to the antinociceptive effect. Interestingly, MoA (100 mg/kg, i.p.) increased the expression of TGF-β in IL-10 knockout mice, which could be a compensation mechanism leading to an antinociceptive effect in the absence of IL-10.

Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture.

As a syndrome, chronic pain comprises physical, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. A rodent model of long-term inflammatory pain, induced by complete Freund's adjuvant (CFA) injection, has previously been shown to cause anhedonia and dysregulated naturalistic behaviors, in a manner similar to animal models of stress. We examined whether this extended to alterations in circadian rhythms and sleep, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG. CFA-induced inflammatory pain profoundly altered sleep architecture in male and female mice. Injection of the hind paw, whether with CFA or saline, reduced some measures of circadian rhythmicity such as variance, period, and amplitude. CFA increased sleep duration primarily in the dark phase, while sleep bout length was decreased in the light and increased in the dark phase. Additionally, CFA reduced wake bout length, especially during the dark phase. Increases in REM and SWS duration and bouts were most significant in the dark phase, regardless of whether CFA had been injected at its onset or 12 hours prior. Taken together, these results indicate that inflammatory pain acutely promotes but also fragments sleep.

Novel analgesic peptide derived from Cinobufacini injection suppressing inflammation and pain via ERK1/2/COX-2 pathway

Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient’s life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1β) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.

Study of Chalcogen Aspirin Derivatives with Carbonic Anhydrase Inhibitory Properties for Treating Inflammatory Pain.

Carbonic anhydrase (CA) inhibitors represent intriguing tools for treating pain. This study aims at studying the pharmacological profile of chalcogen bioisosteres of aspirin, as inhibitors of CA isoforms (hCA I, II, IV, VII, IX, and XII). Our results show that selenoaspirin (5) displayed markedly superior inhibitory potency across all tested isoforms compared to thioaspirin (7) and aspirin, with a strong selectivity against the isoform CA IX. X-ray crystallography confirmed that both compounds bind effectively within the active site of hCA II, revealing unique structural characteristics compared to those of aspirin. In a preclinical model of inflammatory pain, compound 7 exhibited a longer lasting antihyperalgesic effect than aspirin, though with a lower potency. Conversely, compound 5 exhibited both lower potency and efficacy than aspirin in reducing pain, which entailed both adverse effects. Nevertheless, the therapeutic potential of chalcogen-based aspirin derivatives as novel CA inhibitors deserves to be further explored for clinical applications.

THC Vapor Inhalation Attenuates Hyperalgesia in Rats Using a Chronic Inflammatory Pain Model

Humans use cannabinoid drugs to alleviate pain. As cannabis and cannabinoids are legalized in the United States for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain. Here, we tested the effects of repeated ∆9-tetrahydrocannabinol (THC) vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (ie, treated with complete Freund’s adjuvant [CFA]). We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA and also reduces mechanical hypersensitivity in CFA males but not females. Many of the antihyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the cannabinoid type-1 receptor inverse agonist AM251 (1 mg/kg, I.P.) blocks the antihyperalgesic effects of THC vapor in males and females. These data provide a foundation for future work that will explore the cells and circuits underlying the antihyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain. PerspectiveCannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.

Irisin alleviates CFA-induced inflammatory pain by modulating macrophage polarization and spinal glial cell activation

Although the potent anti-inflammatory effects of irisin have been documented in various inflammatory disorders, its efficacy against inflammatory pain remains unexplored. Herein, we examined the therapeutic effects of irisin in a mouse model of inflammatory pain induced by complete Freund’s adjuvant (CFA). Mice were divided into three groups: normal control, CFA-injected (CFA), and CFA plus irisin-treated (CFA+Irisin). The irisin-treated group exhibited a gradual reduction in mechanical allodynia and thermal hyperalgesia when compared with the CFA group. Moreover, treatment with irisin significantly upregulated the expression of M2 macrophage markers (interleukin [IL]-4 and IL-10) and downregulated M1 macrophage markers (IL-1β, IL-6, and tumor necrosis factor-α) in the local paw tissue, dorsal root ganglion, and spinal cord tissue. However, there was no significant difference in the total number of F4/80+ macrophages in the paw tissue and dorsal root ganglion, indicating phenotypic exchange. Treatment with irisin also downregulated the expression of the glial cell activation-related markers Iba-1 and GFAP in the spinal cord tissue. To elucidate the underlying mechanisms, we detected the expression of Toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 5 (IRF5) in paw tissues, dorsal root ganglion, and spinal tissues, revealing that irisin could downregulate the expression of these proteins. Irisin alleviated inflammatory pain by modulating local tissue inflammation and peripheral and central neuroinflammation and reducing glial cell activation and M2 macrophage polarization by modulating the TLR4–MyD88–IRF5 signaling pathway. Accordingly, irisin is a promising candidate for treating inflammatory pain in various diseases.

Exploring the safety of lycorine in the central nervous system and its impact on pain-like behaviors in mice

Alkaloid analgesics have been associated with adverse effects on the central nervous system (CNS). Therefore, it is crucial to characterize the effects of alkaloid analgesics. Plants rich in lycorine, an alkaloid, have shown promise as analgesics. However, the exploration of their CNS side effects, and analgesic effectiveness remains incomplete. The aim of the present study was to investigate the CNS safety profiles of lycorine and its potential analgesic efficacy. Lycorine (3, 10, and 30 mg/kg, intraperitoneal) did not affect motor coordination, and doses of 3 and 10 mg/kg of lycorine did not lead to any impairment in spontaneous locomotor activity. However, the highest dose (30 mg/kg) demonstrated a significant impairment in rearing behavior and an increase in immobility. The safety doses were subsequently used to assess the analgesic efficacy of lycorine in a mouse model of inflammatory pain. Lycorine (1, 3, and 10 mg/kg, intraperitoneal) demonstrated a dose-dependent reduction in pain-like behaviors in formalin-induced mice. In the in vitro study, lycorine regulated immune cells, suggesting its involvement as a cellular mechanism underlying the suppression of pain-like behaviors observed in the formalin model. Overall, our findings delineate the CNS safety range of lycorine in mice and suggest its potential use as an analgesic.

Hormone replacement therapy did not alleviate temporomandibular joint inflammatory pain in ovariectomized rats.

This study had the aim of examining the relationships between variations in estrogen levels resulting from ovariectomy, and estrogen hormone replacement therapy (HRT) in rats subjected to an orofacial inflammatory pain model. Eighty adult female Wistar rats were initially divided into 2 groups: Sham or ovariectomy (OVX-D1). Seven days later (D7), the rats were subjected to an unilateral infiltration of Freund's Complete Adjuvant (CFA) or saline solution into the right temporomandibular joint (TMJ). Then, rats received 17β-estradiol (28µg/kg/day) or placebo for 21days (D10-D31). Nociception was evaluated by the von Frey (VF) and the Hot Plate (HP) tests, and depressive-like behavior by the Forced Swimming (FS) test. On D32 all rats were euthanized and serum, hippocampus and brainstem were collected. The CFA groups presented a mechanical hyperalgesia until day 21 (p ≤ 0.05). No differences were observed among groups in the HP (p = 0.735), and in the immobility and swimming time of the FS (p = 0.800; p = 0.998, respectively). In the brainstem, there was a significant difference in the TNF-ɑ levels (p = 0.043), and a marginal significant difference in BDNF levels (p = 0.054), without differences among groups in the hippocampal BDNF and TNF-ɑ levels (p = 0.232; p = 0.081, respectively). In conclusion, the hormone replacement therapy did not alleviate orofacial pain in ovariectomized rats. However, there is a decrease in brainstem TNF-ɑ levels in the animals submitted to both models, which was partially reverted by HRT.

Coadministration of Novel Analgesic Isovaline with Tramadol Reduces Inflammatory Pain Response in Rats

Aim: Isovaline is a new and promising analgesic with an antinociceptive effect and, unlike µ-opioid agonists, interacts with aminobutyric acid receptors without causing sedation or respiratory depression. In this study, we compare the effect on thermal hyperalgesia and mechanical allodynia coadministration of subcutaneous isovaline and tramadol with individual administrations in a carrageenan-induced hind paw inflammatory pain model in rats. Methods: In this study, isovaline, tramadol, and the combination of isovaline and tramadol were subcutaneously administered to rats with carrageenan-induced inflammation of the hind paws. Hyperalgesia in response to thermal stimuli and allodynia in response to mechanic stimuli were assessed by using a thermal plantar test and a dynamic plantar aesthesiometer, respectively. Results: The administration of subcutaneous isovaline 400mg/kg and tramadol 4mg/ kg combination effect was higher than the other groups on latencies and thresholds (P

Peripheral gating of mechanosensation by glial diazepam binding inhibitor.

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.