Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

Chang, Yu-Wen; Tan, Andrew M.; Saab, Carl Y.; Waxman, Stephen G.

doi:10.1016/j.jpain.2009.06.009

Cited by 75 publications

(67 citation statements)

References 59 publications

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“…No difference in response between NGF-and PBS-injected sides was found (data not shown), suggesting that hyperalgesia spreads to the contralateral side. Similar data have been reported in other animal models of chronic muscle pain (Sluka et al, 2001;Chang et al, 2010). At the pre-NGF time point (day 0, Figure 3a), CUS animals showed enhanced nociception as compared with controls (po0.05).…”

Section: Chronic Widespread Pain Modelsupporting

confidence: 88%

“…This spread of hyperalgesia may be due to activation of nociceptive processes at spinal level, where the complex NGF/tyrosine kinase receptor-A is known to be trafficked and to facilitate the expression of pain-modulating proteins, which may finally lead to a contralateral sensitization. Events of spread hyperalgesia have been reported in other animal models of chronic muscle pain (Sluka et al, 2001;Chang et al, 2010).…”

Section: Discussionmentioning

confidence: 91%

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Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Lomazzo

Bîndilă

Remmers

et al. 2014

Neuropsychopharmacol

121

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The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety-and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamidedegrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.

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Section: Chronic Widespread Pain Modelsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 91%

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Lomazzo

Bîndilă

Remmers

et al. 2014

Neuropsychopharmacol

121

View full text Add to dashboard Cite

show abstract

“…We mapped the cutaneous receptive field surface area of each neuron on an outline of the dorsal surface of the rat hindquarters (shown in Fig. 6) by lightly brushing, pinching, and probing with von Frey filaments (Fischer et al, 2009;Chang et al, 2010). The areas of each receptive field were measured using NIH ImageJ (software download at http://rsbweb.nih.gov/ij/).…”

Section: Methodsmentioning

confidence: 99%

Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain

Tan¹,

Samad²,

Fischer³

et al. 2012

J. Neurosci.

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Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetesinduced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N 6 -[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.

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“…Briefly, WDR neurons were first identified by their general response to a range of low-and high-threshold peripherally evoked stimuli (that is, light brushing with a cottontipped swap and pinching with sharp forceps) applied to each neuron's cutaneous receptive field. Following WDR neuron identification, we mapped the cutaneous receptive field surface area of each neuron on an outline of the dorsal surface of the rat hindquarters by lightly brushing, pinching and probing with von Frey filaments (18,22). The areas of each receptive field were measured using NIH ImageJ (free software available at http://rsbweb.nih.gov/ij/).…”

Section: Electrophysiologymentioning

confidence: 99%

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

Tan

Samad

Dib‐Hajj

et al. 2015

Mol Med

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Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons. Suppression of Nav1.3 activity can attenuate neuropathic pain induced by peripheral nerve injury. Previous studies have shown that expression of Nav1.3 is upregulated in dorsal root ganglion (DRG) neurons of diabetic rats that exhibit neuropathic pain. Here, we hypothesized that viral-mediated knockdown of Nav1.3 in painful diabetic neuropathy would reduce neuropathic pain. We used a validated recombinant adeno-associated virus (AAV)-shRNA-Nav1.3 vector to knockdown expression of Nav1.3, via a clinically applicable intrathecal injection method. Three weeks following vector administration, we observed a significant rate of transduction in DRGs of diabetic rats that concomitantly reduced neuronal excitability of dorsal horn neurons and reduced behavioral evidence of tactile allodynia. Taken together, these findings offer a novel gene therapy approach for addressing chronic diabetic neuropathic pain.

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Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

Cited by 75 publications

References 59 publications

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

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