Chronic intrathecal infusion of gabapentin prevents nerve ligation-induced pain in rats

Chu, Li; Tsaur, Meei‐Ling; Lin, Cheng‐Hsien; Hung, Ying; Wang, T.-Y.; Chen, C.-C.; Cheng, Jen-Kun

doi:10.1093/bja/aer063

Cited by 31 publications

(23 citation statements)

References 36 publications

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“…For instance, the anti-nociceptive and anti-allodynic effectiveness of GBP has been widely supported by studies in animal models of many types of pain induced by peripheral nerve injury such as spinal nerve ligation [47][48][49][50], chronic compression injury [51][52][53][54][55][56] and spared nerve injury [57,58]. Moreover, GBP has also been demonstrated to have anti-allodynic and anti-hyperalgesic effects in animal models of diabetic neuropathy [29] and postherpetic neuralgia [59].…”

Section: Gabapentinoid Insensitivity In Central Neuropathic Pain Of Tmentioning

confidence: 99%

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Yang

et al. 2016

Neurosci. Bull.

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The a 2 d-1 subunit of the voltage-gated Ca 2? channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the a 2 d-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an antiallodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the a 2 d-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the a 2 d-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of a 2 d-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the a 2 d-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor a 2 d-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.Keywords Central post-stroke pain Á Calcium channel a 2 d subunit Á Gabapentinoid Á Thalamic hemorrhagic stroke Á Thalamus Á Spinal dorsal horn

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Section: Gabapentinoid Insensitivity In Central Neuropathic Pain Of Tmentioning

confidence: 99%

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Yang

et al. 2016

Neurosci. Bull.

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“…Other analgesics, such as adenosine, sufentanil, alfentanil and morphine have all been tested intrathecally in animal studies to examine their potential neurotoxicity (Chiari et al, 1999;Sabbe et al, 1994;Westin et al, 2010). Recently, chronic intrathecal infusion of minocycline or gabapentin has been reported to cause no grossly neurotoxicity in animal studies (Chu et al, 2011;Lin et al, 2007), supporting the intrathecal use of these agents for pain management. …”

Section: Intrathecal Neurotoxicity Studiesmentioning

confidence: 88%

“…A point mutation of the arginine 217 of 2 -1 subunit, which is critical for gabapentin binding (Wang et al, 1999), was found to cause a loss of gabapentin-induced analgesia (Field et al, 2006). Recently, chronic intrathecal infusion of gabapentin was found to prevent nerve ligation-induced mechanical allodynia and thermal hyperalgesia without causing obvious neuropathological changes in spinal cord and cauda equine (Chu et al, 2011). Gabapentin has been found to attenuate morphine-induced tolerance (Lin et al, 2005) and this finding may encourage the combined use of gabapentin with morphine in the treatment of neuropathic pain.…”

Section: 2 Subunit Of Camentioning

confidence: 99%

Intrathecal Studies on Animal Pain Models

Cheng¹

2012

Pain Management - Current Issues and Opinions

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“…This subunit is the binding site for gabapentinoid drugs in the dorsal horn. In preclinical models, gabapentin and pregabelin have been shown to have potent effect in a variety ofhyperalgesic pain [175][176][177][178] Preclinical results indicate adequate spinal pK with a very hydrophilic cLogP (-1.13). In a recent study, however, it was unexpectedly reported that intrathecal infusion of gabapentin failed to alter pain assessments in human patients suffering from a variety of neuropathic and non-neuropathic pain states [179].…”

Section: Future Directions For Spinal Calcium Channel Blockersmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Chronic intrathecal infusion of gabapentin prevents nerve ligation-induced pain in rats

Abstract: We showed a preventative effect of intrathecal gabapentin on the development of nerve injury-induced mechanical allodynia and thermal hyperalgesia. Our data suggest that continuous intrathecal gabapentin may be considered as an alternative for the prevention of nerve injury-induced pain.

Cited by 31 publications

References 36 publications

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

Intrathecal Studies on Animal Pain Models

Current and Future Issues in the development of spinal agents for the management of pain

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