Background: Pannexin1 (Panx1) is a membrane channel expressed in different cells of the nervous system and is involved in several pathological conditions, including pain and inflammation. At the central nervous system, the role of Panx1 is already well-established. However, in the periphery, there is a lack of information regarding the participation of Panx1 in neuronal sensitization. The dorsal root ganglion (DRG) is a critical structure for pain processing and modulation. For this reason, understanding the molecular mechanism in the DRG associated with neuronal hypersensitivity has become highly relevant to discovering new possibilities for pain treatment. Here, we aimed to investigate the role of Panx1 in acute nociception and peripheral inflammatory and neuropathic pain by using two different approaches. Methods: Rats were treated with a selective Panx1 blocker peptide (10Panx) into L5-DRG, followed by ipsilateral intraplantar injection of carrageenan, formalin, or capsaicin. DRG neuronal cells were pre-treated with 10Panx and stimulated by capsaicin to evaluate calcium influx. Panx1 knockout mice (Panx1-KO) received carrageenan or capsaicin into the paw and paclitaxel intraperitoneally. The von Frey test was performed to measure the mechanical threshold of rats’ and mice’s paws before and after each treatment. Results: Pharmacological blockade of Panx1 in the DRG of rats resulted in a dose-dependent decrease of mechanical allodynia triggered by carrageenan, and nociception decreased in the second phase of formalin. Nociceptive behavior response induced by capsaicin was significantly lower in rats treated with Panx1 blockade into DRG. Neuronal cells with Panx1 blockage showed lower intracellular calcium response than untreated cells after capsaicin administration. Accordingly, Panx1-KO mice showed a robust reduction in mechanical allodynia after carrageenan and a lower nociceptive response to capsaicin. A single dose of paclitaxel promoted acute mechanical pain in wildtype (WT) but not in Panx1-KO mice. Four doses of chemotherapy promoted chronic mechanical allodynia in both genotypes, although Panx1-KO mice had significant ablation in the first eight days. Conclusion: Our findings suggest that Panx1 is critical for developing peripheral inflammatory pain and acute nociception involving transient receptor potential vanilloid subtype 1 (TRPV1) but is not essential for neuropathic pain chronicity.

Unsuccessful anesthesia often occurs under an inflammatory tissue environment, making dentistry treatment extremely painful and challenging. Articaine (ATC) is a local anesthetic used at high (4%) concentrations. Since nanopharmaceutical formulations may improve the pharmacokinetics and pharmacodynamics of drugs, we encapsulated ATC in nanostructured lipid carriers (NLCs) aiming to increase the anesthetic effect on the inflamed tissue. Moreover, the lipid nanoparticles were prepared with natural lipids (copaiba (Copaifera langsdorffii) oil and avocado (Persia gratissima) butter) that added functional activity to the nanosystem. NLC-CO-A particles (~217 nm) showed an amorphous lipid core structure according to DSC and XDR. In an inflammatory pain model induced by λ-carrageenan in rats, NLC-CO-A improved (30%) the anesthetic efficacy and prolonged anesthesia (3 h) in relation to free ATC. In a PGE2-induced pain model, the natural lipid formulation significantly reduced (~20%) the mechanical pain when compared to synthetic lipid NLC. Opioid receptors were involved in the detected analgesia effect since their blockage resulted in pain restoration. The pharmacokinetic evaluation of the inflamed tissue showed that NLC-CO-A decreased tissue ATC elimination rate (ke) by half and doubled ATC’s half-life. These results present NLC-CO-A as an innovative system to break the impasse of anesthesia failure in inflamed tissue by preventing ATC accelerated systemic removal by the inflammatory process and improving anesthesia by its association with copaiba oil.

Platelet-rich plasma (PRP) is a biological blood-derived therapeutic that releases several proteins in injured tissue, regulating the inflammatory process and triggering tissue anabolism. Outside of the central nervous system (CNS), these platelets represent the major source of brain-derived neurotrophic factor (BDNF). The associated anti-inflammatory, antiapoptotic, and antioxidant properties of this neurotrophin could have a potential applicability applied in the pathophysiology of osteoarthritis (OA). In osteoarthritic joints, it is suggested that synovial cells release BDNF, being found higher concentrations of this protein in the patient’s synovial fluid. Thus, considering platelets as an important therapeutic source of BDNF and the potential role of this neurotrophin in regulate joint homeostasis and OA outcomes, this study aimed to evaluate the contribution of BDNF in PRP repair activities on an experimental model of osteoarthritis (EOA) induced by monoiodine acetate (MIA) insult. Initially, the characterization of the PRP was performed, obtaining a leukocyte-poor-platelet-rich plasma (LP-PRP). After, in vitro analysis indicated that platelets activated by Ca²⁺ release BDNF, and suppression of M1 macrophage polarization induced by LP-PRP is dependent on BDNF-TrkB receptor. The behavioral and ex-vivo analyses in EOA animals showed that functional recovery in gait parameters and mitigation on tissue damage induced by LP-PRP, such as downregulation of inflammatory cytokines (TNF-α), reduction of joint pain and tissue damage (OARSI score and neuronal injury through ATF-3 [+] cells), depends on Trk-B receptor. Thus, the results indicate that BDNF and Trk-B receptor appear to be essential in the mechanisms of joint repair induced by LP-PRP with implications on joint functional recovery as well. These findings contribute to clarifying the role of BDNF in joint homeostasis, repurposing its restricted therapeutic properties in the CNS to repair functions in non-neuronal tissues that could be an option for chronic pain management in osteoarthritis (OA).