CCI and hind paw withdraw threshold to mechanical

CCI (chronic
constriction injury) reduces the HCN1 and HCN2 mRNA expression

Liu
et al demonstrated that neuropathy induced by CCI (chronic constriction injury)
in left sciatic nerve decreased the expression of HCN1 and HCN2 mRNA in
peripheral nerve system and spinal cord. The hind paw withdraw latency to
thermal stimulation and hind paw withdraw threshold to mechanical stimulation
were decreased in injured rats. The chronic constriction injury was induced by
exposing the left sciatic nerve at the middle of the thigh by blunt dissection through
biceps femoris. 4 ligatures (4.0 chromic gut) with 1 mm spacing were tied
loosely around about 7 mm of exposed nerve, adjacent  to the sciatic’s trifurcation (Bennett et
al.,1987). The paw withdraw latency and paw withdraw threshold were decreased
in chronic constriction injured rats at 7th, 10th and 14th
day after injury (Liu et al., 2016). The author reported that perfusion with 50
uM ZD7288 (specific Ih blocker) for 15 min significantly decreased the resting
membrane potential and increased the action potential rising time. It also
caused a significant decrease in the repetitive firing number and the V0.5
(the membrane potential at which HCN channel was half-activated). This
indicated that the activated HCN channels help to stabilize the resting
membrane potential in the resting state and drive the membrane potential
depolarization to the threshold of action potential, causing in the elevation
of neuronal excitability (Tu et al., 2004). CCI induced nerve degeneration,
which was observed by performing nissl staining method on dorsal root
ganglions. In CCI dorsal root ganglions, degenerated nerve cells was found,
which was indicated by the disappearance of nissl bodies and lost of nucleoli
14 days after CCI (Liu et al., 2016).

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Mechanism:

 In CCI
induced neuropathy, the injured sciatic nerve leads to increased spontaneous
firing or alterations in the conduction of neurotransmitter, resulting in
chronic or persistent pain. HCN is correlated to Ih (Hyperpolarization-activated
current) current, a cation current which is activated by membrane
hyperpolarization, results in the formation of resting membrane potential (Liu
et al., 2016). The activation of I h is very
sensitive to intracellular adenylate cyclase and cAMP activities. Increase in
cAMP (during ?-receptor activation) lead to depolarization, whereas decrease in
cAMP (during muscarinic receptor activation) lead to hyperpolarization (Ingram
et al., 1996). Cui et al reported that Prostaglandin E2 causes
the activation of adenylate cyclase to increase intracellular cyclic AMP, which
in turn activates protein kinase A. The activation of protein kinase A leads to
increased levels of protein phosphorylation, this results in the enhancement of
neuronal sensitivity to excitatory chemical agents (Cui et al., 1995).Thus the prostaglandins
enhance the excitability of sensory neurons and this sensitization may occur
due to the suppression of a sustained or delayed rectifier type of K+ channel,
that modulates the threshold of AP firing. Therefore the inhibition of these K+ channels
results in increased generation of Aps. Suppression of I K
through PGE2 causes the reduction
in the firing threshold of the neurons which further leads to increase in
membrane resistance (Baccaglini et al., 1983).In DRG neurons after the nerve
injury if the spontaneous action potential is negative due to hyperpolarization
and lasts long enough to activate Ih, then this Ih will contribute to facilitation
of the firing discharges. Therefore the discharge frequency of spontaneously
active DRG neurons may be reduced by Ih inhibition through a2-adrenoceptor
activation (Yagi et al., 1998).