| Abstract |
Although pain is described as an unpleasant, with serious consequences for the
individual experience, it can be vital since in many cases it warns of the existence of
significant damage. According to Woolf (Woolf, 2010) pain can be divided into
nociceptive, neuropathic and inflammatory. In the present study we focused on
inflammatory pain which is a consequence of various pathological conditions such as
viral or bacterial infection, tissue injury or autoimmune diseases. The main feature of
inflammatory pain is the activation of the immune system which aims to repair the
injured tissue or inhibit the infection.
Dehydroepiandrosterone (DHEA) is a steroid hormone derived from adrenal glands
with strong neuroprotective and immunomodulatory properties. DHEA is also
produced and acts in the brain and other structures of the nervous system. DHEA has a
wide range of actions including its beneficial effect on pain. DHEA acts by interacting
with both cytoplasmic and membrane receptors, including neurotrophin receptors TrkA
and p75NTR. However, DHEA is rapidly metabolized into androgens and estrogens,
which limits its therapeutic use. For this reason, new molecules have been developed
similar to DHEA, which retain its beneficial effects but lack its ability to be metabolized
to sex hormones. Recent studies have shown that the analog of DHEA, BNN27, binds
to neurotrophin receptors. BNN27 has neuroprotective properties preventing neuronal
apoptosis, additionally to its strong immunomodulatory properties, affecting, among
other things, the production and release of inflammatory molecules.
Based on the above, the purpose of this study was to evaluate the role of BNN27 on
inflammatory pain. For this purpose, the model of inflammatory hyperalgesia caused
by induction of inflammation and the application of a thermal stimulus at the site of
inflammation in wild-type mice was applied. Inflammation and swelling in mice were
induced by intraplantar administration of Complete Freund's Adjuvant, CFA, and BNN27 was administered at different concentrations (10, 50, 100 mg/ kg) and intervals.
Threshold of inflammatory hyperalgesia, the size of edema and the expression of factors
that contribute / participate in pain process were then assessed.
Our results showed that BNN27 increases the inflammatory pain threshold without
affecting edema. In addition, it induces the release of inflammatory agents (IL-6, TNF-
α, IL-10, NGF, iNOS) 6 hours following the induction of inflammation, a phenomenon
that subsides within 24 hours from the onset of the inflammatory response. In addition,
BNN27 stimulates the synthesis of opioid peptides and μ opioid receptor in the inflamed
paw. Opioid peptides and their receptors seem to mediate the action of BNN27 on pain
since pharmacological inhibition of opioid receptors reduces the analgesic effect of
BNN27 in a significant way. The mechanism of action of BNN27 also includes the
reduction of nerve growth factor (NGF) mRNA levels in the dorsal root ganglia
(DRGs), in which the latter acts by enhancing the transmission of pain signals to the
brain, and activation of the TrkA receptor and the downstream AKT2 signaling
pathway.
Finally, we studied the effect of BNN27 on T-lymphocytes in vitro. T-lymphocytes are
involved in the inflammatory process since they release pro-inflammatory cytokines
and opioid peptides at the site of inflammation. We found that different concentrations
of BNN27 (10-6, 10-7 and 10-8 M) affect T-lymphocyte proliferation and survival in a
different way. Indeed, BNN27 at the concentration of 10-7 M increases the proliferation
rate of T-lymphocytes in contrast to concentrations of 10-6 Μ and 10-8 M that decrease
their proliferation rate. Co-administration of BNN27 at a concentration of 10-8 M with
a TrkA receptor inhibitor (10-6 M) further reduces T-lymphocyte proliferation rate.
Finally, BNN27 stimulates the release of cytokines and opioid peptides from T-
lymphocytes, while co-administration with the TrkA inhibitor inhibits this effect. In conclusion, our results demonstrate that BNN27 has a beneficial effect on
inflammatory hyperalgesia. The action of BNN27 is mediated by the TrkA receptor and
involves the inhibition of NGF synthesis in DRGs. In addition, its mechanism of action
includes the inhibition of cytokine release and the induction of opioid peptides synthesis
in the inflamed tissue, most likely by T-lymphocytes, as BNN27 affects the
proliferation rate and the release of these cytokines and opioid peptides from this cell
type
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