Analgesic and Anti-Inflammatory Effects of the Synthetic Neurosteroid Analogue BNN27 during CFA-Induced Hyperalgesia

Abstract

Dehydroepiandrosterone (DHEA), an adrenal and neurosteroid hormone with strong neuroprotective and immunomodulatory properties, and ligand for all high-affinity neurotrophin tyrosine kinase receptors (Trk), also exerts important effects on hyperalgesia. Its synthetic, 17-spiro-epoxy analogue, BNN27, cannot be converted to estrogen or androgen as DHEA; it is a specific agonist of TrkA, the receptor of pain regulator Nerve Growth Factor (NGF), and it conserves the immunomodulatory properties of DHEA. Our study aimed to evaluate the anti-nociceptive and anti-inflammatory properties of BNN27 during Complete Freund’s Adjuvant (CFA)-induced inflammatory hyperalgesia in mice. Hyperalgesia was evaluated using the Hargreaves test. Inflammatory markers such as cytokines, NGF and opioids were measured, additionally to corticosterone and the protein kinase B (AKT) signaling pathway. We showed for the first time that treatment with BNN27 reversed hyperalgesia produced by CFA. The effect of BNN27 involved the inhibition of NGF in the dorsal root ganglia (DRG) and the increased synthesis of opioid peptides and their receptors in the inflamed paw. We also found alterations in the cytokine levels as well as in the phosphorylation of AKT2. Our findings strongly support that BNN27 represents a lead molecule for the development of analgesic and anti-inflammatory compounds with potential therapeutic applications in inflammatory hyperalgesia.

Bone marrow‐derived mesenchymal stem cells attenuate complete Freund's adjuvant‐induced inflammatory pain by inhibiting the expression of P2X3

“…Accumulating evidence has indicated that the injection of CFA into the rodent hind paw could lead to sustained inflammation characterized by persistent hypersensitivities 19,20 . For example, nerve growth factor (NGF) is considered a crucial factor in inflammation and hyperalgesia, and its level was elevated in the paws of inflamed rats treated with CFA 34 . In addition, elevated NGF expression was also detected in rodent DRG after administration of CFA, which induces sensitization of transient potential receptor V1 (TRPV1) and/or A1 (TRPA1)‐positive DRG sensory neurons and in turn facilitates the transmission of pain signals to the central nervous system 35 .…”

“… 19 , 20 For example, nerve growth factor (NGF) is considered a crucial factor in inflammation and hyperalgesia, and its level was elevated in the paws of inflamed rats treated with CFA. 34 In addition, elevated NGF expression was also detected in rodent DRG after administration of CFA, which induces sensitization of transient potential receptor V1 (TRPV1) and/or A1 (TRPA1)‐positive DRG sensory neurons and in turn facilitates the transmission of pain signals to the central nervous system. 35 Thus, the CFA‐induced chronic pain rat model is commonly regarded as an inflammatory pain model.…”

Optogenetic modulation of electroacupuncture analgesia in a mouse inflammatory pain model

“…Inflammation also induced mechanical and thermal hyperalgesia accompanied by increased IL-6 and TNF-α in the mice plasma, suggesting EA as an anti-inflammatory technique. Recently articles reported that local inflammation in mice increased circulating IL‑6 and TNF-α levels 34 . Additionally, although the administration of IL-6 induced mechanical and thermal hyperalgesia, IL-6 blockage produced analgesic effects 35 .…”

mRNA expression of CRF family members in urothelial bladder cancer

“…All the tissues had 2-3 mm thickness. Total RNA was extracted from the tissues with TRIzol reagent (Invitrogen Life Technologies), and cDNAs were synthesized using TAKARA PrimeScript 1st strand cDNA synthesis kit (Takara Bio) (19). Expression of each gene of interest was determined using SYBR Green master mix (Kapa Biosystems) containing a specific set of primers in a final volume of 10 µl.…”