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

Lin, Huai-San; Huang, Yu‐Hsin; Chao, Tzu-Hao Harry; Lin, Wen-Ying; Sun, Wei‐Zen; Yen, Chen‐Tung

doi:10.1186/1744-8069-10-63

Cited by 30 publications

(24 citation statements)

References 66 publications

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“…Furthermore, we found the S1HL area began to cooperate with the AIC under the neuropathic pain condition; however, the overall S1HL activity did not differ between the SNI and sham groups. In our previous study, we observed no variations in S1HL responses to von Frey hair stimulation between SNI and naïve rats [ 34 ]. Whether and how the S1 is involved in allodynia is the subject of debate.…”

Section: Discussionmentioning

confidence: 95%

Plasticity changes in forebrain activity and functional connectivity during neuropathic pain development in rats with sciatic spared nerve injury

2018

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Neuropathic pain is a major worldwide health problem. Although central sensitization has been reported in well-established neuropathic conditions, information on the acute brain activation patterns in response to peripheral nerve injury is lacking. This study first mapped the brain activity in rats immediately following spared nerve injury (SNI) of the sciatic nerve. Using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD-fMRI), we observed sustained activation in the bilateral insular cortices (ICs), primary somatosensory cortex (S1), and cingulate cortex. Second, this study sought to link this sustained activation pattern with brain sensitization. Using manganese-enhanced magnetic resonance imaging (MEMRI), we observed enhanced activity in the ipsilateral anterior IC (AIC) in free-moving SNI rats on Days 1 and 8 post-SNI. Furthermore, enhanced functional connectivity between the ipsilateral AIC, bilateral rostral AIC, and S1 was observed on Day 8 post-SNI. Chronic electrophysiological recording experiments were conducted to confirm the tonic neuronal activation in selected brain regions. Our data provide evidence of tonic activation-dependent brain sensitization during neuropathic pain development and offer evidence that the plasticity changes in the IC and S1 may contribute to neuropathic pain development.

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Section: Discussionmentioning

confidence: 95%

Plasticity changes in forebrain activity and functional connectivity during neuropathic pain development in rats with sciatic spared nerve injury

2018

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“…It is important to point out that pharmacokinetics of gabapentin in humans and rodents is different [61], which may explain higher systemic and intrathecal doses used in this and other rodent studies [17; 20; 23; 24; 38; 68]. For intra-rACC injections, we used 10 and 100 μg in anesthetized and awake rats, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…We used a dose 5-10 fold higher to account for faster rate of elimination in rats [61; 65]. This dose is based on previous studies that used intraperitoneal or subcutaneous dosing of 100 mg/kg in rats [17; 23; 24; 38] At this dose, gabapentin did not produce sedation [23]. Moreover, i.p.…”

Section: Methodsmentioning

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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“…Symptoms may include hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli, as well as spontaneous pain (2). An estimated 7-8% of the general population suffers from mild to moderate forms of neuropathic pain, and 5% may be severely affected by it (3). Such pain is a major health problem that substantially reduces quality of life for the afflicted individuals and poses a significant economic burden to the health system and society (2).…”

Section: Introductionmentioning

confidence: 99%

Chronic nerve injury-induced Mas receptor expression in dorsal root ganglion neurons alleviates neuropathic pain

Zhao

Qin

Liu

et al. 2015

Experimental and Therapeutic Medicine

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Neuropathic pain, which is characterized by hyperalgesia, allodynia and spontaneous pain, is one of the most painful symptoms that can be experienced in the clinic. It often occurs as a result of injury to the peripheral nerves, dorsal root ganglion (DRG), spinal cord or brain. The renin-angiotensin system (RAS) plays an important role in nociception. As an essential component of the RAS, the angiotensin (Ang)-(1-7)/Mas axis may be involved in antinociception. The aim of the present study was to explore the expression pattern of Mas in DRG neurons following chronic nerve injury and examine the effects of Mas inhibition and activation on neuropathic pain in a chronic constriction injury (CCI) rat model. The results showed, that compared with the sham group, CCI caused a time-dependent induction of Mas expression at both the mRNA and the protein levels in DRG neurons. Consistent with the results, isolated DRG neurons showed a time-dependent increase in Ang-(1-7) binding on the cell membrane following the CCI surgery, but not the sham surgery. Compared with the sham control groups, CCI significantly decreased the paw withdrawal latency and threshold, and this was markedly improved and aggravated by intrathecal injection of the selective Mas agonist Ang-(1-7) and the selective Mas inhibitor D-Pro7-Ang-(1-7), respectively. In conclusion, this study has provided the first evidence, to the best of our knowledge, that the Mas expression in DRG neurons is time-dependently induced by chronic nerve injury and that the intrathecal activation and inhibition of Mas can improve and aggravate CCI-induced neuropathic pain, respectively. This study has provided novel insights into the pathophysiological process of neuropathic pain and suggests that the Ang-(1-7)/Mas axis could be an effective therapeutic target for neuropathic pain, warranting further study.

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

Cited by 30 publications

References 66 publications

Plasticity changes in forebrain activity and functional connectivity during neuropathic pain development in rats with sciatic spared nerve injury

Plasticity changes in forebrain activity and functional connectivity during neuropathic pain development in rats with sciatic spared nerve injury

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

Chronic nerve injury-induced Mas receptor expression in dorsal root ganglion neurons alleviates neuropathic pain

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