Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain

Molecular Pain, Nov 2010

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 α2δ-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 anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-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 α2δ-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 α2δ-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 α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.molecularpain.com/content/pdf/1744-8069-6-83.pdf

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. - 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)


This is a preview of a remote PDF: http://www.molecularpain.com/content/pdf/1744-8069-6-83.pdf

Naoki Kusunose, Satoru Koyanagi, Kengo Hamamura, Naoya Matsunaga, Miyako Yoshida, Takahiro Uchida, Makoto Tsuda, Kazuhide Inoue, Shigehiro Ohdo. Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain, Molecular Pain, 2010, pp. 83, 6, DOI: 10.1186/1744-8069-6-83