Role of descending noradrenergic system and spinal α 2 -adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse

Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
British Journal of Pharmacology (Impact Factor: 4.84). 04/2005; 144(5):703-14. DOI: 10.1038/sj.bjp.0706109
Source: PubMed


1. To gain further insight into the mechanisms underlying the antihyperalgesic and antiallodynic actions of gabapentin, a chronic pain model was prepared by partially ligating the sciatic nerve in mice. The mice then received systemic or local injections of gabapentin combined with either central noradrenaline (NA) depletion by 6-hydroxydopamine (6-OHDA) or alpha-adrenergic receptor blockade. 2. Intraperitoneally (i.p.) administered gabapentin produced antihyperalgesic and antiallodynic effects that were manifested by elevation of the withdrawal threshold to a thermal (plantar test) or mechanical (von Frey test) stimulus, respectively. 3. Similar effects were obtained in both the plantar and von Frey tests when gabapentin was injected intracerebroventricularly (i.c.v.) or intrathecally (i.t.), suggesting that it acts at both supraspinal and spinal loci. This novel supraspinal analgesic action of gabapentin was only obtained in ligated neuropathic mice, and gabapentin (i.p. and i.c.v.) did not affect acute thermal and mechanical nociception. 4. In mice in which central NA levels were depleted by 6-OHDA, the antihyperalgesic and antiallodynic effects of i.p. and i.c.v. gabapentin were strongly suppressed. 5. The antihyperalgesic and antiallodynic effects of systemic gabapentin were reduced by both systemic and i.t. administration of yohimbine, an alpha2-adrenergic receptor antagonist. By contrast, prazosin (i.p. or i.t.), an alpha1-adrenergic receptor antagonist, did not alter the effects of gabapentin. 6. It was concluded that the antihyperalgesic and antiallodynic effects of gabapentin are mediated substantially by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors.

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Available from: Hideki Ono, Jan 27, 2014
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    • "In rats, gabapentin produced increases in BOLD signal intensity in both the thalamus and the periaqueducal grey (Governo et al., 2008), two brain regions rostral to the obex. In mice with peripheral nerve injuries, Tanabe et al. (2005) demonstrated that gabapentin acts supraspinally to activate the descending noradrenergic bulbospinal pathway, suppressing the activation of spinal nociceptive neurons via activation of a 2 adrenoceptors. Interestingly, these effects of gabapentin on descending noradrenergic pathways were observed only with neuropathic pain models and did not affect the withdrawal threshold in normal rats (Tanabe et al., 2008). "
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    ABSTRACT: Gabapentin is a structural analogue of gamma-amino-butyric acid with anticonvulsant activity. Recently, indications for its use were extended to the management of acute pain in the postoperative period. The effects of pre-administration of gabapentin on the depressive action of intravenous morphine were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats with either an intact neuraxis or a brainstem previously transected at the level of the obex. As previously reported, 6 mg/kg intravenous morphine both increased the threshold and decreased the slope of the stimulus-response recruitment curve. The C-fibre reflex was not modified following intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01-7.5 mg/kg) not only antagonized the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10-50 mg/kg), gabapentin pre-treatment potentiated the depressive effect of morphine. In obex-transected rats, the facilitation of the C-fibre reflex, seen following 1 mg/kg gabapentin and 6 mg/kg morphine, disappeared and was replaced by a strong reinforcement of the depressive effect of morphine. It is concluded that a strong synergy between the effects of gabapentin and morphine can be seen at the spinal level. However, radically opposite effects with supraspinal origins thwart this mechanism. From the clinical standpoint, these results incite cautiousness in the use of combinations of gabapentin and opioids.
    Full-text · Article · May 2011 · Neuropharmacology
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    • "ck test ) ( Chien and Pasternak 1994 ; Cendán et al . 2005b ) , but data on their effect on mechanical nociceptive pain have not been previously reported . Regarding the drugs used as controls , our results fully agree with those previously reported , since neither gabapentin nor rofecoxib affected mechanical nociception in nonsensitized animals ( Tanabe et al . 2005 ; Padi and Kulkarni 2004 ) , whereas clonidine reduced mechanical pain in these animals ( Honda et al . 2002 ; Paqueron et al . 2003 ) . Haloperidol and HP - Met - II showed affinity for σ 1 receptors at nanomolar concentrations ( Cobos et al . 2007 ; this study ) and for D 2 and D 3 receptors at nanomolar ( HP ) and low micromolar ( HP"
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    ABSTRACT: We evaluated the effects of haloperidol and its metabolites on capsaicin-induced mechanical hypersensitivity (allodynia) and on nociceptive pain induced by punctate mechanical stimuli in mice. Subcutaneous administration of haloperidol or its metabolites I or II (reduced haloperidol) dose-dependently reversed capsaicin-induced (1 microg, intraplantar) mechanical hypersensitivity of the hind paw (stimulated with a nonpainful, 0.5-g force, punctate stimulus). The order of potency of these drugs to induce antiallodynic effects was the order of their affinity for brain sigma-1 (sigma(1)) receptor ([(3)H](+)-pentazocine-labeled). Antiallodynic activity of haloperidol and its metabolites was dose-dependently prevented by the selective sigma(1) receptor agonist PRE-084, but not by naloxone. These results suggest the involvement of sigma(1) receptors, but discard any role of the endogenous opioid system, on the antiallodynic effects. Dopamine receptor antagonism also appears unlikely to be involved in these effects, since the D(2)/D(3) receptor antagonist (-)-sulpiride, which had no affinity for sigma(1) receptors, showed no antiallodynic effect. None of these drugs modified hind-paw withdrawal after a painful (4 g force) punctate mechanical stimulus in noncapsaicin-sensitized animals. As expected, the control drug gabapentin showed antiallodynic but not antinociceptive activity, whereas clonidine exhibited both activities and rofecoxib, used as negative control, showed neither. These results show that haloperidol and its metabolites I and II produce antiallodynic but not antinociceptive effects against punctate mechanical stimuli and suggest that their antiallodynic effect may be due to blockade of sigma(1) receptors but not to dopamine receptor antagonism.
    Full-text · Article · Apr 2009 · Psychopharmacology
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    • "The anti-epileptic agent gabapentin has demonstrated uniform analgesic efficacy in animal models of neuropathic pain (Chen and Pan, 2005; Hayashida et al., 2007b; Pan et al., 1999; Tanabe et al., 2005) and in patients with chronic pain (Laird and Gidal, 2000). Recently, we and others have shown that gabapentin acts on supraspinal structures to stimulate a bulbospinal-spinal noradrenergic-cholinergic pathway in rodents after peripheral nerve injury (Hayashida et al., 2007b; Takasu et al., 2006; Tanabe et al., 2005). Stimulation of α 2 -adrenoceptors by spinally released noradrenaline results not only in inhibition of spinal nociceptive neurons (Jones, 1991), but also in activation of cholinergic circuits (Eisenach, 1999). "
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    ABSTRACT: We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.
    Preview · Article · Oct 2008 · European Journal of Pharmacology
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