Response to spinal cord stimulation in variants of the spared nerve injury pain model

doi:10.1016/j.neulet.2006.02.028

Neuroscience Letters

Volume 400, Issues 1–2, 29 May 2006, Pages 115-120

https://doi.org/10.1016/j.neulet.2006.02.028 Get rights and content

Abstract

Spinal cord stimulation (SCS) is a treatment given to patients with drug-resistant neuropathic pain, in particular pain resulting from peripheral nerve injury. However, the reasons why some patients develop neuropathic pain and why SCS is not effective in all patients with this chronic pain are not fully understood. The present study compares the response to SCS and the yield of neuropathic animals in variants of the spared nerve injury (SNI) model introduced by Decosterd and Woolf (I. Decosterd, C.J. Woolf, Spared nerve injury: an animal model of persistent peripheral neuropathic pain, Pain 87 (2000) 149–158). Sprague–Dawley rats were prepared with various types of lesions of different branches of the sciatic nerve and then tested for paw mechanical hypersensitivity. A miniature electrode system for SCS was implanted at the T10-T11 vertebral level. Stimulation was applied in awake, freely moving animals with parameters comparable to those employed clinically. Suppression of paw hypersensitivity was considered a positive response to SCS. The incidence of mechanical hypersensitivity (“allodynia”) in the different models was: SNI 53%; peroneal axotomy 45%; tibial axotomy 68%; tibial tight ligation 73% and partial tibial tight ligation 50%. “Mirror phenomena” with contralateral paw hypersensitivity was present in about 20% of the animals. The response to SCS differed between models with the lowest response rate in the original SNI model (8%) while the others demonstrated rates in the order of 40–50%. There was a tendency that the efficacy of SCS in suppressing allodynia was inversely related to the severity of hypersensitivity. In conclusion, modifications of the SNI model provide a reproducible incidence of neuropathic hypersensitivity and an increased responsiveness to SCS. These variants may prove suitable for future research on the mechanisms involved in pain relief with SCS.

Section snippets

Acknowledgements

This study has been supported by grants from Karolinska institutets fonder and from Medtronic Europe SA.

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Citation Excerpt :
There was a 10-min pause for each measurement. The cutoff time was set at 20 s (Li et al., 2006). The rats were fully anesthetized using pentobarbital (50 mg/kg, i.p. injection).
Chronic neuropathic pain has demonstrated that coexisting psychiatric disorders are associated with disability and poorer treatment outcomes. Hyperpolarization-activated cyclic nucleotide-gated (HCN, Ih) channels play a major role in pain via hyperexcitability and facilitation of ectopic firing in neurons. Neuronal hyperexcitability contributes to pain maintenance and anxiety/depression. GABA-mediated inhibitory postsynaptic neurotransmission in the brain is impaired in the pathophysiology of chronic neuropathic pain with comorbidity mood disorders. Currently, interaction of HCN channels and GABAergic synaptic transmission inhibition in neuropathic pain and the associated comorbidity anxiety/depression mechanism remains relatively unknown. To address this, the HCN channel inhibitor, ZD7288, was administrated to Wistar Kyoto (WKY) rats after spared nerve injury (SNI). Our findings show that intracerebroventricular injection of ZD7288 concurrently attenuates co-existing nociceptive and depression-like behaviors, and increases glutamicacid decarboxylase (GAD67/65) expression and GABA levels in the hippocampus and thalamus with High-performance liquid chromatography technique. It suggests that inhibition of HCN channels is likely to decrease the hyperexcitability of neurons in rat SNI and improve the level of GABA. Further, HCN channel may offer a new strategy to alleviate both neuropathic pain and comorbidity for depression.
Mirror-image pain after nerve reconstruction in rats is related to enhanced density of epidermal peptidergic nerve fibers
2015, Experimental Neurology
Mirror-image pain is a phenomenon in which unprovoked pain is detected on the uninjured contralateral side after unilateral nerve injury. Although it has been implicated that enhanced production of nerve growth factor (NGF) in the contralateral dorsal root ganglion is important in the development of mirror-image pain, it is not known if this is related to enhanced expression of nociceptive fibers in the contralateral skin.
Mechanical and thermal sensitivity in the contralateral hind paw was measured at four different time points (5, 10, 20 and 30 weeks) after transection and immediate end-to-end reconstruction of the sciatic nerve in rats. These findings were compared to the density of epidermal (peptidergic and non-peptidergic) nerve fibers on the contralateral hind paw.
Mechanical hypersensitivity of the contralateral hind paw was observed at 10 weeks PO, a time point in which both subgroups of epidermal nerve fibers reached control values. Thermal hypersensitivity was observed with simultaneous increase in the density of epidermal peptidergic nerve fibers of the contralateral hind paw at 20 weeks PO. Both thermal sensitivity and the density of epidermal nerve fibers returned to control values 30 weeks PO.
We conclude that changes in skin innervation and sensitivity are present on the uninjured corresponding side in a transient pain model. Therefore, the contralateral side cannot serve as control. Moreover, the current study confirms the involvement of the peripheral nervous system in the development of mirror-image pain.
A continuous spinal cord stimulation model attenuates pain-related behavior in vivo following induction of a peripheral nerve injury
2015, Neuromodulation
Models that simulate clinical conditions are needed to gain an understanding of the mechanism involved during spinal cord stimulation (SCS) treatment of chronic neuropathic pain. An animal model has been developed for continuous SCS in which animals that have been injured to develop neuropathic pain behavior were allowed to carry on with regular daily activities while being stimulated for 72 hours.
Sprague-Dawley rats were randomized into each of six different groups (N = 10–13). Three groups included animals in which the spared nerve injury (SNI) was induced. Animals in two of these groups were implanted with a four-contact electrode in the epidural space. Animals in one of these groups received stimulation for 72 hours continuously. Three corresponding sham groups (no SNI) were included. Mechanical and cold-thermal allodynia were evaluated using von Frey filaments and acetone drops, respectively. Mean withdrawal thresholds were compared. Statistical significance was established using one-way ANOVAs followed by Holm-Sidak post hoc analysis.
Continuous SCS attenuates mechanical allodynia in animals with neuropathic pain behavior. Mechanical withdrawal threshold increases significantly in SNI animals after 24 and 72 hours stimulation vs. SNI no stimulation (p = 0.007 and p < 0.001, respectively). SCS for 24 and 72 hours provides significant increase in mechanical withdrawal thresholds relative to values before stimulation (p = 0.001 and p < 0.001, respectively). Stimulation did not provide recovery to baseline values. SCS did not seem to attenuate cold-thermal allodynia.
A continuous SCS model has been developed. Animals with neuropathic pain behavior that were continuously stimulated showed significant increase in withdrawal thresholds proportional to stimulation time.
Is constant current or constant voltage spinal cord stimulation superior for the suppression of nociceptive visceral and somatic stimuli? A rat model
2012, Neuromodulation
This study compares the effects of constant current (CC) and constant voltage (CV) spinal cord stimulation (SCS) at various frequencies and intensities on standard nociceptive measurements in rats, the visceromotor reflex (VMR) and neuronal activity, during noxious visceral and somatic stimuli.
Abdominal muscle electromyographic activity changes were measured to indicate VMR, and extracellular activity of L6-S2 spinal neurons was recorded during somatic (pinching) and noxious visceral stimulation (colorectal distension [CRD], 60 mmHg) in anesthetized rats. A stimulating (unipolar ball) electrode at L2-L3 delivered CC- or CV-SCS at varied frequencies and intensities.
CC-SCS reduced VMR evoked by CRD significantly more than CV-SCS (p < 0.05). For neuronal activity, high-frequency CC-SCS (40 and 100 Hz) and CV-SCS (100 Hz) effectively reduced intraspinal somatic nociceptive transmission more than low-frequency SCS (2 Hz). No significant differences were observed between the effects of CC- and CV-SCS on spontaneous activity and nociceptive responses of spinal neurons to noxious CRD following short- (five to ten minutes) or long-term (20–30 min) SCS.
Although high-frequency CC- and CV-SCS may be more useful for the management of somatic pain, CC-SCS may be more effective for treating complex pain systems like visceral hypersensitivity.
Bipolar spinal cord stimulation attenuates mechanical hypersensitivity at an intensity that activates a small portion of A-fiber afferents in spinal nerve-injured rats
2011, Neuroscience
Citation Excerpt :
These findings support the predictions from a computer model for SCS (Holsheimer, 1998; Feirabend et al., 2002). SCS often fails to achieve complete inhibition of mechanical hypersensitivity in animal behavioral studies; that is, PWT does not return to pre-injury levels (Li et al., 2006; Schechtmann et al., 2008; Maeda et al., 2008). Similarly, in clinical situations, SCS usually produces only partial pain relief (Carter, 2004; Meyerson and Linderoth, 2006).
Spinal cord stimulation (SCS) is used clinically to treat neuropathic pain states, but the precise mechanism by which it attenuates neuropathic pain remains to be established. The profile of afferent fiber activation during SCS and how it may correlate with the efficacy of SCS-induced analgesia are unclear. After subjecting rats to an L5 spinal nerve ligation (SNL), we implanted a miniature quadripolar electrode similar to that used clinically. Our goal was to determine the population and number of afferent fibers retrogradely activated by SCS in SNL rats by recording the antidromic compound action potential (AP) at the sciatic nerve after examining the ability of bipolar epidural SCS to alleviate mechanical hypersensitivity in this model. Notably, we compared the profiles of afferent fiber activation to SCS between SNL rats that exhibited good SCS-induced analgesia (responders) and those that did not (nonresponders). Additionally, we examined how different contact configurations affect the motor threshold (MoT) and compound AP threshold. Results showed that three consecutive days of SCS treatment (50 Hz, 0.2 ms, 30 min, 80–90% of MoT), but not sham stimulation, gradually alleviated mechanical hypersensitivity in SNL rats. The MoT obtained in the animal behavioral study was significantly less than the Aα/β-threshold of the compound AP determined during electrophysiological recording, suggesting that SCS could attenuate mechanical hypersensitivity with a stimulus intensity that recruits only a small fraction of the A-fiber population in SNL rats. Although both the MoT and compound AP threshold were similar between responders and nonresponders, the size of the compound AP waveform at higher stimulation intensities was larger in the responders, indicating a more efficient activation of the dorsal column structure in responders.
Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction
2011, Annals of Anatomy
Citation Excerpt :
In the model, the tibial and peroneal nerves are transected while preventing reinnervation by ligation of their stumps even as the sural nerve is left intact (Decosterd and Woolf, 2000). A number of modifications exist for the SNI model in which sciatic nerve branches are injured through transection or ligation (Lee et al., 2000; Li et al., 2006a). Although interruption of axonal continuity after nerve transection results in blockade of retrograde axonal transport of neurotrophins and signal molecules to the neuronal bodies, an interruption of the blood–nerve barrier in the distal stump (Mellick and Cavanagh, 1968; Olsson, 1968a; Omura et al., 2004) may allow transport of the molecules through blood circulation.
Wallerian degeneration is a cascade of stereotypical events in reaction to injury of nerve fibres. These events consist of cellular and molecular alterations, including macrophage invasion, activation of Schwann cells, as well as neurotrophin and cytokine upregulation.
This review focuses on cellular and molecular changes distal to various types of peripheral nerve injury which simultaneously contribute to axonal regeneration and neuropathic pain induction. In addition to the stereotypical events of Wallerian degeneration, various types of nerve damage provide different conditions for both axonal regeneration and neuropathic pain induction. Wallerian degeneration of injured peripheral nerve is associated with an inflammatory response including rapid upregulation of the immune signal molecules like cytokines, chemokines and transcription factors with both beneficial and detrimental effects on nerve regeneration or neuropathic pain induction.
A better understanding of the molecular interactions between the immune system and peripheral nerve injury would open the possibility for targeting these inflammatory mediators in therapeutic interventions. Understanding the pleiotropic effects of cytokines/chemokines, however, requires investigating their highly specific pathways and precise points of action.

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¹: Present address: Department of Neurosurgery, Shanghai Second Medical University Ruijin Hospital, Shanghai, PR China.

²: Present address: Laboratory of Sensory System, Institute of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

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Response to spinal cord stimulation in variants of the spared nerve injury pain model

Abstract

Section snippets

Acknowledgements

Pain

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Neuroscience

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Eur. J. Pharm.

Trends Neurosci.

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Eur. J. Pain