Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Abstract

The anticonvulsant gabapentin (GBP) has been shown effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the ␣ 2 ␦ subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC 50 ϭ 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC 50 Ͼ 10,000 nM), which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. Systemic administration of GBP or (1S,3R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1R,3R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1S,3R)3-MeGBP, was blocked by i.t. injection of the GABA B receptor antagonist [3-[[(3,4-Systemic GBP or (1S,3R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1R,3R)3-MeGBP was ineffective. However, both (1S,3R)3-MeGBP and (1R,3R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1R,3R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1S,3R)3-MeGBP had a significant, albeit transient, effect. Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to ␣ 2 ␦ binding, likely does not completely account for the mechanism of action of GBP.Gabapentin (GBP; Neurontin) is an anticonvulsant that has found increased utility for the treatment of clinical neuropathic pain. Although originally developed for the treatment of spasticity and epilepsy, recent attention has focused on the utility of GBP for the treatment of neuropathic pain based on its efficacy and minimal side-effect profile in clinical trials (Rice and Maton, 2001). In rodent neuropathic pain models, GBP effectively attenuates thermal and mechanical hypersensitivity following peripheral nerve ligation (Xiao and Bennett, 1996;Hunter et al., 1997;Hwang and Yaksh, 1997). GBP has also been shown to inhibit thermal and mechanical hyperalgesia following carrageenan-induced inflammation (Field et al., 1997b;Lu and Westlund, 1999); however, other studies have reported limited effectiveness of GBP for inflammatory pain (Gould et al., 1997;Patel et al., 2001). Additionally, GBP inhibits spontaneous nociceptive behaviors and mechanical hyperalgesia produced by intraplantar formalin or surgical incision, respectively (Field et al., 1997a,b). The antinociceptive effects of GBP in models of neuropathic, inflammatory, and surgical pain appear to be selective for injury-induced hypersensitivity, ...

Mechanisms of the Antinociceptive Action of Gabapentin

“…Nevertheless, it seems that activating Ih channels would result in pronociceptive but not antinociceptive action. First, the amplitude of Ih in DRG neurons isolated from the nerve-ligated neuropathic rats was significantly increased and the Ih channel blocker ZD7288 reversed the nociceptive response in this pain model (115), in which gabapentin is an effective analgesic (17,84). Recently, Sun et al (116) found that ZD7288, by inhibiting Ih current, suppressed the ectopic discharges of injured DRG neurons in a gabapentin-sensitive neuropathic pain model.…”

“…It seems that gabapentin is effective in inflammatory-and tissue-injury induced pain models but not in acute physiological pain models (14,17,19) (Table 1).…”

Gabapentin and Pregabalin for the Treatment of Neuropathic Pain: A Review of Laboratory and Clinical Evidence

“…However a particular dose of gabapentin given by the same route, in the same model, will not necessarily produce the same effect on pain behaviours across all studies. In the SNL model, for example, IP 100 mg/kg gabapentin elicited a 51% reversal of the mechanical withdrawal threshold (17), whereas others found a complete reversal of the mechanical withdrawal threshold to the preinjury baseline responses following IP 100 mg/kg gabapentin (21). Similarly, in the CCI model, IP 50 mg/kg gabapentin produced a 31% reversal of the injuryevoked heat hyperalgesia (19), whereas IP 25 mg/kg gabapentin was also found to elicit a complete reversal of this pain behaviour (6).…”

“…In comparison, all eight studies that measured mechanical allodynia found an inhibition of this pain behaviour following systemic gabapentin, although the magnitude of reversal was variable. One-half of these studies reported a partial (50% or less) reversal (6,(17)(18)(19), whereas the other one-half reported a 80% to 100% reversal of mechanical allodynia by gabapentin (13,14,20,21). Two studies have examined systemic gabapentin on nerve injury-evoked heat hyperalgesia (6,19), one reporting a partial (31%) reversal (19) and the other a complete reversal of this pain behaviour (6).…”

Gabapentin-Lactam Induces Dendritic Filopodia and Motility in Cultured Hippocampal Neurons

“…Gabapentin [1-(aminomethyl)-cyclohexane acetic acid] is widely used in the treatment of epilepsy and chronic neuropathic pain syndromes (Andrews and Fischer, 1994;Tremont-Lukats et al, 2000;Urban et al, 2005). Lately, it has been applied in the treatment of limb tremor (Zesiewicz et al, 2005).…”