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Mechanisms of the Antinociceptive Action of Gabapentin

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Mechanisms of the Antinociceptive Action of Gabapentin J Pharmacol Sci 100, 000 – 000 (2006) Journal of Pharmacological Sciences ©2006 The Japanese Pharmacological Society Critical Review Mechanisms of the Antinociceptive Action of Gabapentin Jen-Kun Cheng1,2,3 and Lih-Chu Chiou1,4,* 1Institute and 4Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan 2Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan 3Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan Received October 12, 2005 Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABAB receptors consisting of GABAB1a and GABAB2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K+ channels, activating hyperpolarization-activated cation channels, and modulating Ca2+ current by selectively binding 3 2+ to the specific binding site of [ H]gabapentin, the α2δ subunit of voltage-dependent Ca channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive 2+ action mechanisms of gabapentin and suggest that the α2δ subunit of spinal N-type Ca channels is very likely the analgesic action target of gabapentin. Keywords: gabapentin, GABAB receptor, NMDA receptor, KATP channel, 2+ α2δ subunit of Ca channels 1. Introduction actively studied. Several hypothesis were raised, which have been summarized in the comprehensive review of Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid Taylor et al. in 1998 (1). The cellular action mechanisms (Neurontin)®, was originally developed as a chemical of gabapentin were also recently reveiwed (7 – 9). analogue of γ-aminobutyric acid (GABA) (Fig. 1) to Different mechansims might be involved in the different reduce the spinal reflex for the treatment of spasticity actions of gabapentin (10). The clinical uses of and was found to have anticonvulsant activity in various gabapentin in the management of chronic neuropathic seizure models (1). In addition, it also displays anti- pain have been previoulsy reviewed (11, 12). In this nociceptive activity in various animal pain models. review, we summarized and discussed the recent Clinically, gabapentin is indicated as an add-on medica- progresses in the studies investigating the antinocicep- tion for the treatment of partial seizures (2) and neuro- pathic pain (3). It was also claimed to be beneficial in several other clinical disorders such as anxiety (4), bipolar disorder (5), and hot flashes (6). The possible mechanisms or targets involved in the multiple therapeutic actions of gabapentin have been *Corresponding author. [email protected] Published online in J-STAGE: DOI: 10.1254/jphs.CR0050020 Fig. 1. Chemical structures of γ-aminobutyric acid (GABA) and Invited article gabapentin. 1 2 J-K Cheng and L-C Chiou tive action machanisms of gabapentin to elucidate the Table 1. Antinociceptive effects of gabapentin in various animal most likely analgesic action target(s) of gabapentin. pain models Pain model Dose (route) Reference 2. Analgesic effects of gabapentin Gabapentin ineffective 2-1. Animal studies Acute nociception After gabapentin was found to have an analgesic Hot plate test 0.1 – 100 nmol (i.t.) 168 effect in patients with intractable neuropathic pain (13), 10 – 100 mg/kg (i.p.) 168 its antinociceptive effects had been reported in several Tail-flick test 200 µg (i.t.) 15 animal pain models, including the phase 2, but not phase 30 – 300 mg/kg (i.p.) 24 1, of formalin inflammatory (14 – 19), neuropathic Paw pressure test 30 – 300 mg/kg (s.c.) 19 (17, 20 – 26), postoperative (27, 28), lumbar adhesive Plantar thermal test 30 – 300 mg/kg (s.c.) 19 arachnoiditis (29), and cancer-induced bone (30) pain 10 – 300 µg (i.t.) 14 models (Table 1). It seems that gabapentin is effective Warm water tail 100 mg/kg (i.p.) 17 in inflammatory- and tissue-injury induced pain models withdrawal test but not in acute physiological pain models (14, 17, 19) Gabapentin effective (Table 1). Gabapentin is effective when given systemically (10 – Inflammatory pain 300 mg/kg) or intrathecally (10 – 300 µg) (Table 1). Formalin test (phase 2) 100 mg/kg (i.p.) 17 However, it seems that much higher efficacy can be 10 – 300 mg/kg (s.c.) 19 achieved for gabapentin via intrathecal administration. 6–200µg (i.t.) 15 In the postoperative pain model, only 19% of the 10 – 300 µg (i.t.) 14 maximal possible antiallodynic effect was observed at 6–600µg (local) 16 the highest tested dose of gabapentin when it was given Carrageenan-induced 10 – 100 mg/kg (s.c.) 19 intraperitoneally (31). However, intrathecal gabapentin 1–100µg (i.t.) 19 could produce up to 90% – 100% the maximal possible Freund’s complete 30 – 250 mg/kg (s.c.) 21 antiallodynic effect in the same model (28). Similar adjuvant test findings were also reported in certain neuropathic pain Neuropathic pain models such as partial sciatic nerve ligation (21) and Spinal nerve ligation 34 mg/kg (i.p.) a 24 chronic constriction injury (25) models. Takasaki et al. 10 – 100 mg/kg (i.p.) 17 (32) reported that gabapentin was effective when given 10 – 300 µg (i.t.) 26 orally and intrathecally, but not intraventricularlly, intra- Partial sciatic nerve ligation 10 – 250 mg/kg (s.c.) 21 cisternally, or intraplantarlly in relieving the nociceptive 10 – 300 µg (i.t.) 21 behaviors induced by transdermal infection with herpes Chronic constriction injury 103 mg/kg (i.p.)a 24 simplex virus. It seems that the spinal cord is an impor- 30 – 300 mg/kg (i.p.) 25 tant site for the systemic analgesic action of gabapentin. 1–4µmol (i.t.) 25 However, since gabapentin is also effective in the Diabetic neuropathy 10 – 100 mg/kg (p.o.) 22 management of migraine and trigeminal neuralgia (see 1–100µg (i.t.) 22 section 2-2), the contribution of the supraspinal site to Postherpetic neuralgia 30 – 60 mg/kg (i.p.) 23 the systemic analgesic action of gabapentin cannot be µ ruled out. 10 – 30 g (i.t.) 23 Trigeminal neuralgia 30 – 50 mg/kg (i.p.) 20 2-2. Clinical studies Postoperative pain 3 – 30 mg/kg (s.c.) 27 Clinically, gabapentin has been reported to be effec- 10 – 100 µg (i.t.) 28 tive in the following pain status, including reflex Cancer-induced bone pain 30 mg/kg (s.c.) 30 sympathetic dystrophy (33), trigeminal neuralgia (34), postherpetic neuralgia (35, 36), diabetic neuropathy (36, Lumbar adhesive 60 nmol (i.t.) 29 arachnoiditis pain 37), migraine (38), acute pain in herpes zoster infection a (39), and other neuropathic pain status (40, 41) : ED50 (Table 2). Gabapentin is also effective in the postopera- tive pain management in different surgeries such as breast (42, 43), hysterectomy (44, 45), cholecystectomy opioid consumption was found to be reduced in several (46), spinal (47), and knee (48) surgeries (Table 2). The pain states when gabapentin was co-administered clini- Antinociceptive Mechanisms of Gabapentin 3 Table 2. Clinical studies in the analgesic actions of gabapentin Pain status Dosage Patient No. Side effects Reference Neuropathic pain Diabetic neuropathy 900 – 3600 mg/day 165 dizziness 37 somnolence Diabetic neuropathy a 900 – 3200 mg/day 35 sedation 36 dry mouth Lyme borreliosis (late stage) 500 – 1200 mg/day 10 40 Postherpetic neuralgia up to 3600 mg/day 229 somnolence 35 dizziness ataxia Postherpetic neuralgia a 900 – 3200 mg/day 22 sedation 36 dry mouth Trigeminal neuralgia 2 34 Postoperative pain a Radical mastectomy 1200 mg (pre-operative) 70 42 Breast cancer surgery 1200 mg/day 75 43 Hysterectomy 1200 mg (initial) 80 44 600 mg (maitaining) Laparoscopic cholecystectomy 300 mg (pre-operative) 459 sedation 46 nausea vomiting Spinal surgery 1200 mg (pre-operative) 50 47 Knee ligament repair 1200 mg (pre-operative) 40 48 Herpes zoster (acute stage) 900 mg 26 39 Migraine prophylaxis 400 – 1200 mg/day 63 somnolence 38 dizziness tremor fatigue ataxia a: reducing opioids comsumption cally (Table 2). On the other hand, gabapentin might 4. Mechanisms of actions of gabapentin also be helpful in reducing the dependence and tolerance of opioids, as suggested by animal studies (49, 50). It 4-1. GABAergic system seems that gabapentin is relatively a pretty safe drug in 4-1-1. GABAA receptors terms of its tolerable effective doses with minor un- Although being developed as a brain penetrant wanted or side effects clinically (Table 2). analogue of GABA, gabapentin showed little affinity at GABAA or GABAB receptors in the initial binding 3. Other clinical implications of gabapentin study (57). The antinociceptive effects of intrathecal gabapentin in the formalin test (58) and L5/6 nerve In addition to the management of seizures and pain, ligation pain model (26) were unaffected by the several clinical indications for gabapentin have also GABAA-receptor antagonist bicuculline. Therefore, it is been implied, including anxiety (4), bipolar depression generally believed that the GABAA receptor is not (5), hot flashes (6), social phobia (51), essential tremor involved in the actions of gabapentin (1). In the post- (52), ataxia in cortical cerebellar atrophy (53), hiccup operative pain model, where the GABAA-receptor (54), post cardiac surgery diaphragmatic spasm (55), and agonist isoguvacine is ineffective, bicuculline also failed antipsychotic-induced akathisia (56). to reverse the antinociceptive effect of intrathecal gabapentin (59). 4-1-2. GABAB receptors GABAB receptors are functional in a heterodimeric 4 J-K Cheng and L-C Chiou form consisting of GABAB1 and GABAB2 subunits (60).
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