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Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain
Naoki Kusunose
0
Satoru Koyanagi
0
Kengo Hamamura
0
Naoya Matsunaga
0
Miyako Yoshida
Takahiro Uchida
Makoto Tsuda
Kazuhide Inoue
Shigehiro Ohdo
0
0
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University
,
Fukuoka
,
Japan
Background: Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel a2-1 subunit. Results: Mice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the antiallodynic effects varied according to its dosing time. The protein levels of a2-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of a2-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when a2-1 subunit protein was abundant. Conclusions: These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of a2-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.
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Background
Neuropathic pain is a chronic condition that occurs
after bone compression in cancer, diabetes, herpesvirus
infection and auto immune disease [1]. Millions of
patients in the world presently endure neuropathic pain
[2]. One troublesome hallmark symptom of neuropathic
pain is hypersensitivity to normally innocuous stimuli, a
condition known as tactile allodynia that is often
refractory to NSAIDs and opioids [3].
The GABA analogue gabapentin was originally
developed to treat epilepsy [4], but it is now widely used to
alleviate neuropathic pain [3]. Accumulating evidence
from diverse animal models of neuropathic pain suggests
that the anti-allodynic effects of gabapentin are
associated with the modulation of neurotransmitter release or
neuronal excitability resulting from alterations in Ca2+
currents [5,6]. The a2 subunit, but not the pore-forming
a1 or b subunits, of voltage-dependent Ca2+ channels
(VDCC) in the spinal cord and dorsal root ganglion
(DRG) is upregulated in gabapentin-sensitive pain models
such as mechanical- and diabetic-neuropathic types, but
not in the gabapentin-insensitive chemical model of
neuropathic pain [7-9]. The time course of upregulation of
the a2 subunit in DRG is parallel to the duration of
neuropathic pain induced by nerve injury [9]. Gabapentin
is thought to modulate Ca2+ currents by binding to the
a2-1 subunit of VDCC [10-12].
Gabapentin is now widely used to alleviate
neuropathic pain because it is well-tolerated, easily titrated,
and has interacts with few drugs [13]. However, higher
doses of gabapentin can cause side effects such as
dizziness, drowsiness, and peripheral edema [14]. The
appropriate dosing schedule of gabapentin has not been
well-established yet.
One approach to increasing the effect of
pharmacotherapy is to administer drugs at the times of day
when they are most effective and/or best tolerated.
Circadian variations in biological functions such as gene
expression and protein synthesis are thought to be
important factors affecting the efficacy of drugs. In fact,
the expression levels of proteins related to the
regulation of the susceptibility to the drugs and their
pharmacokinetics oscillated in a circadian time-dependent
manner [15-17]. It is thus possible that the
pharmacological effects of gabapentin could be more improved by
choosing the appropriate dosing time. To test this
possibility, we explored whether the anti-allodynic effects of
gabapentin in a mouse model of neuropathic pain
was changed according to its dosing time. The
mechanism underlying dosing time-dependent changes in
the anti-allodynic effects of gabapentin was investigated
from the perspectives of pharmacokinetics and
pharmacodynamics.
Results
Time-dependent changes in allodynic behavior of mice
To create an animal model of neuropathic pain, we
prepared mice undergone partial sciatic nerve ligation
(PSL). As reported previously [18], the paw withdrawal
threshold (PWT) of PSL mice significantly decreased
after nerve injury (P < 0.05; Figure 1A). The decrease in
PWT continued until at least 3 weeks (data not shown).
O (...truncated)