Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose-response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose-response curves (10-13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2-7-fold shift for ip and combo, 2-3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule-protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose-response curve should be performed in an appropriate behavioral task.
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PMID:Injection route and TLR9 agonist addition significantly impact heroin vaccine efficacy. 2451 71

Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem; however, our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study, we examined the role of TLR9 in CIPN induced by paclitaxel in WT and Tlr9 mutant mice of both sexes. Baseline pain sensitivity was not affected in either Tlr9 mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of WT and Tlr4 KO mice but failed to do so in Tlr9 mutant mice. Moreover, Trpv1 KO or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or Tlr9 mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to DRGs in both sexes, and this infiltration was not affected by Tlr9 mutation. Paclitaxel treatment also upregulated TNF and CXCL1 in macrophage cultures and DRG tissues in both sexes, but these changes were compromised by Tlr9 mutation in male animals. Intraplantar adoptive transfer of paclitaxel-activated macrophages evoked mechanical allodynia in both sexes, which was compromised by Tlr9 mutation or by treatment with TLR9 inhibitor only in male animals. Finally, TLR9 antagonism reduced paclitaxel-induced mechanical allodynia in female nude mice (T-cell and B-cell deficient). Together, these findings reveal sex-dimorphic macrophage TLR9 signaling in chemotherapy-induced neuropathic pain.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect in cancer patients undergoing clinical chemotherapy treatment regimens. The role of sex dimorphism with regards to the mechanisms of CIPN and analgesia against CIPN remains unclear. Previous studies have found that the infiltration of immune cells, such as macrophages into DRGs and their subsequent activation promote CIPN. Interestingly, the contribution of microglia to CIPN appears to be limited. Here, we show that macrophage TLR9 signaling promotes CIPN in male mice only. This study suggests that pathways in macrophages may be sex-dimorphic in CIPN. Our findings provide new insights into the role of macrophage signaling mechanisms underlying sex dimorphism in CIPN, which may inspire the development of more precise and effective therapies.
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PMID:Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice. 3127 Jan 60