Affiliation:
1. Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings SD 57007, United States
2. Department of Pharmacology and Therapeutics, University of Florida, Gainesville FL 32610, United States
Abstract
Background & Objective:
Hyperalgesia and allodynia are frequent symptoms of inflammatory
pain. Neuronal excitability induced by the Brain-Derived Neurotrophic Factor (BDNF)-tyrosine
receptor kinase B (TrkB) cascade has a role in the modulation of inflammatory pain. The effects
of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide
(TQS), an α7 nicotinic Acetylcholine Receptor Positive Allosteric Modulator (nAChR PAM), on
hippocampal BDNF, cation-chloride cotransporters, NKCC1 and KCC2, expression in inflammatory
pain are not known. The objective of the study was to determine the effects of TQS on BDNF,
NKCC1, and KCC2 expression in the hippocampus following lipopolysaccharide (LPS)-induced allodynia
and hyperalgesia in a mouse model of inflammatory pain.
Methods:
Mice were treated with TQS followed by LPS (1 mg/kg, ip) administration. The effects
of TQS on mRNA and BDNF in the hippocampus were examined using qRT-PCR and Western
blot, respectively. Immunoreactivity of BDNF, NKCC1, and KCC2 in the hippocampus was measured
after LPS administration using immunofluorescence assay. Allodynia and hyperalgesia were
determined using von Frey filaments and hot plate, respectively.
Results:
The LPS (1 mg/kg) upregulates mRNA of BDNF and downregulates mRNA of KCC2 in
the hippocampus and pretreatment of TQS (4 mg/kg) reversed the effects induced by LPS. In addition,
the TQS decreased LPS-induced upregulation of BDNF and p-NKCC1 immunoreactivity in
the dentate gyrus and CA1 region of the hippocampus. BDNF receptor (TrkB) antagonist, ANA12
(0.50 mg/kg), and NKCC1 inhibitor bumetanide (30 mg/kg) reduced LPS-induced allodynia and
hyperalgesia. Blockade of TrkB with ANA12 (0.25 mg/kg) enhanced the effects of TQS (1 mg/kg)
against LPS-induced allodynia and hyperalgesia. Similarly, bumetanide (10 mg/kg) enhanced the
effects of TQS (1 mg/kg) against allodynia and hyperalgesia.
Conclusion:
These results suggest that antinociceptive effects of α7 nAChR PAM are associated
with downregulation of hippocampal BDNF and p-NKCC1 and upregulation of KCC2 in a mouse
model of inflammatory pain.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,General Neuroscience
Cited by
6 articles.
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