Gabapentin‐induced pharmacodynamic effects in the spinal nerve ligation model of neuropathic pain

Hooker, Bradley A.; Tobón, Gabriel J.; Baker, Scott J.; Zhu, Chang; Hesterman, Jacob; Schmidt, Karl F.; Rajagovindan, Raj; Chandran, Prasant; Joshi, Sunil Kumar; Bannon, Anthony W.; Hoppin, Jack; Beaver, John D.; Fox, Gerard B.; Day, Mark L.; Upadhyay, Jaymin

doi:10.1002/j.1532-2149.2013.00364.x

Cited by 15 publications

(16 citation statements)

References 75 publications

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“…Gabapentin is an anticonvulsant and at analgesic doses readily crosses the blood brain barrier in both humans and rodents [4; 36]. Effects of systemic gabapentin on BOLD activity have been demonstrated using phMRI in naïve and SNL rats [22; 27]. Importantly, neuroimaging studies in healthy human subjects have demonstrated reduced mechanical stimulus-mediated BOLD fMRI activity during the oral gabapentin session in the insular cortex, the ACC and the SII [31].…”

Section: Discussionmentioning

confidence: 99%

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Bannister

Navratilova

et al. 2017

Pain

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Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients.

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Section: Discussionmentioning

confidence: 99%

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Bannister

Navratilova

et al. 2017

Pain

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“…Because the paw withdrawal ratio reduced substantially, the decreased glucose metabolism might reflect reduced neural activity. Hooker et al [ 15 ] demonstrated that the cerebellum showed activation of BOLD signals after GBP infusion. This discrepancy might be due to that their animals were anesthetized, whereas our animals were awake.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin Reverses Central Hypersensitivity and Suppresses Medial Prefrontal Cortical Glucose Metabolism in Rats with Neuropathic Pain

et al. 2014

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BackgroundGabapentin (GBP) is known to suppress neuropathic hypersensitivity of primary afferents and the spinal cord dorsal horn. However, its supra-spinal action sites are unclear. We identify the brain regions where GBP changes the brain glucose metabolic rate at the effective dose that alleviates mechanical allodynia using 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning.ResultsComparing the PET imaging data before and after the GBP treatment, the spared nerve injury-induced increases of glucose metabolism in the thalamus and cerebellar vermis were reversed, and a significant decrease occurred in glucose metabolism in the medial prefrontal cortex (mPFC), including the anterior cingulate cortex. GBP treatment also reversed post-SNI connectivity increases between limbic cortices and thalamus.ConclusionsOur results indicate that GBP analgesic effect may be mediated by reversing central hypersensitivity, and suppressing mPFC, a crucial part of the cortical representation of pain, in the brain.

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“…Furthermore, phMRI in rats and humans has shown activation of similar brain regions in response to buprenorphine [18]. Additional analgesic medications have been evaluated using phMRI in rats to study chronic pain models and the effects of the medication on brain systems (e.g., gabapentin in spinal nerve ligation model [85]; celecoxib in an OA model [192]; buprenorphine in healthy rats [18]; ketamine in healthy rats [39]; and remifentanil in healthy rats [118]). Using phMRI in preclinical models of chronic pain may also assist in identifying the circuits involved in adverse events [38, 120].…”

Section: Recommendationsmentioning

confidence: 99%

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

Smith

Dworkin

Turk

et al. 2017

The Journal of Pain

124

108

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Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the US Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: (1) sensory testing, (2), skin punch biopsy, and (3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: (1) diagnostic, (2) prognostic, (3) predictive, and (4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials.

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Gabapentin‐induced pharmacodynamic effects in the spinal nerve ligation model of neuropathic pain

Abstract: Using phMRI and functional connectivity analysis approaches, the PD effects of gabapentin in a preclinical neuropathic pain state were characterized. Furthermore, the current results offer insights on which brain systems gabapentin directly or indirectly acts upon.

Cited by 15 publications

References 75 publications

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Gabapentin Reverses Central Hypersensitivity and Suppresses Medial Prefrontal Cortical Glucose Metabolism in Rats with Neuropathic Pain

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

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