Background & Objective:
Hyperalgesia and allodynia are frequent symptoms of inflammatory pain. Neuronal
excitability induced by 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]quinoline8-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 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.
Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal
