Combined approaches for the relief of spinal cord injury-induced neuropathic pain

doi:10.1016/j.ctim.2015.12.021

Complementary Therapies in Medicine

Volume 25, April 2016, Pages 27-33

https://doi.org/10.1016/j.ctim.2015.12.021 Get rights and content

Highlights

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The pharmacological therapy for the neuropathic pain has unwanted side effects.
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The sensory modulation in not unique way for the neuropathic pain treatment.
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Acupuncture modulates pain and psychiatric disorders in neuropathic pain.
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Acupuncture has effects on pain and psychiatric modulation is mediated by GABA system.
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Acupuncture has great effects at pain and psychiatric disorders, and suggests the feasibility for neuropathic pain therapy.

Abstract

The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain.

It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient.

In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.

Introduction

Traumatic spinal cord injury (SCI) causes multiple dysfunctions in the sensory systems, such as neuronal hyperexcitability in the central nervous system (CNS) including the spinal cord, brain stem, thalamus, and cortex, which consequently result in neuropathic pain.1, 2, 3, 4, 5, 6 In patients with SCIs, abnormalities in the sensory functions persist throughout the patients’ lives and adversely influence the quality of life, often resulting in suicides.7, 8 Previous studies have shown that SCIs cause consistent neuronal hypersensitivity and increased withdrawal response to external stimuli, such as allodynia (non-painful stimuli are perceived as painful) and hyperalgesia (painful stimuli are perceived as extremely painful); these are interpreted as neuropathic pain-like behaviors due to the alteration of the neurochemical and neuroanatomical distribution following SCI.9, 10, 11

The candidate substances for the treatment of the SCI-induced neuropathic pain are well documented; experimental rodent-SCI model studies have revealed the cellular mechanisms involved in the various SCI conditions. The medications predominantly used currently for neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, such as GABApentin, pregabalin, lamotrigine, and amitriptyline; the pain relief achieved through these medications suggests that the psychiatric aspects of a patient are important factors in neuropathic pain treatment.12, 13, 14, 15, 16, 17 A majority of the pain patients, however, report dissatisfaction and adverse outcomes such as fever, nausea, dizziness, rashes, weakness, drowsiness, and other psychiatric disorders.18, 19, 20 Taken together, these facts suggest that the effective treatment of SCI-induced neuropathic pain can be achieved in conjunction with the management of the sensory and psychiatric aspects of the patients, and that it is essential to develop non-pharmacological therapeutic approaches such as alternative medicine, to facilitate the therapeutic effect of the pharmacological approaches for neuropathic pain treatment.

In this review, we address the attenuation of the SCI-induced neuropathic pain through the management of the sensory and psychiatric behaviors involving acupuncture and pharmacological treatment to increase the efficacy of neuropathic pain treatment.

Section snippets

Acupuncture therapy

In oriental medicine, acupuncture is the most well-known therapeutic approach for the management of several pathophysiological conditions including both sensory abnormalities and psychiatric disorders such as pain and anxiety/depression, respectively.21, 22, 23 The critical aspect of acupuncture therapy is the stimulation of the acupuncture needle inserted at a specific acupoint, which is a suitable spot for acupuncture on the body, rather than the needle insertion itself. Adequate acupuncture

Psychiatric relief of pain

Neuropathic pain caused by neurotraumas, such as SCI, result in multifunctional disorders including those of the somatosensory, emotional, and cognitive aspects. Chronic neuropathic pain persists throughout the patients’ lives, and medications are essential to alleviate the extreme pain condition that follow SCIs. The pain patients strongly express their motivation to alleviate or attenuate neuropathic pain in order to achieve the feelings of comfort and safety.⁴⁸ Therefore, relief from the

Acupuncture and reward mechanism

Classically, studies on the acupuncture-induced reward behaviors have been focused on the addictive drugs, such as alcohol, cocaine, and morphine; whereas, little is known about the acupuncture-induced reward behaviors in neuropathic pain conditions. Chronic alcohol intake causes the decrease of the GABA neuronal activity and the firing of the dopamine neurons in the VTA followed by the increase of the dopamine in the NAc via the upregulation of the glutamate receptors such as NMDAR1 and

Conclusion

The modulation of sensory events is not the only method for achieving pain relief. Pain patients undergoing sensory modulation treatment still complain of dissatisfaction with the extent of pain relief and adverse effects from the medications, which suggest that alternative approaches for neuropathic pain treatment are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important

Competing interests

There are no competing financial interests.

Author’s contribution

Chae Ha Yang contributed to the acupuncture-reward section and revised the manuscript.

Young S. Gwak contributed to the design of the manuscript and wrote the section on GABA and spinal cord injury pain.

Hee Young Kim contributed to the section on the pain management mechanism of acupuncture and revised the manuscript.

Bong Hyo Lee contributed to the section on the mechanism of acupuncture and revised the manuscript.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (NRF-2015R1A5A7037508) and the NRF-2014R1A1A4A01004179 and 2014R1A2A2A01005851.

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Opioids are not universally effective for treating neuropathic pain following spinal cord injury (SCI), a finding that we previously demonstrated in a rat model of SCI. The aim of this study was to determine analgesic response of morphine-responsive and nonresponsive SCI rats to adjunct treatment with dopamine modulators and to establish if the animal groups expressed distinct metabolomic profiles. Thermal thresholds were tested in female Long Evans rats (N = 45) prior to contusion SCI, after SCI and following injection of morphine, morphine combined with dopamine modulators, or dopamine modulators alone. Spinal cord and striatum samples were processed for metabolomics and targeted mass spectrometry. Morphine provided analgesia in 1 of 3 of SCI animals. All animals showed improved analgesia with morphine + pramipexole (D3 receptor agonist). Only morphine nonresponsive animals showed improved analgesia with the addition of SCH 39166 (D1 receptor antagonist). Metabolomic analysis identified 3 distinct clusters related to the tyrosine pathway that corresponded to uninjured, SCI morphine-responsive and SCI morphine-nonresponsive groups. Mass spectrometry showed matching differences in dopamine levels in striatum and spinal cord between these groups. The data suggest an overall benefit of the D3 receptor system in improving analgesia, and an association between morphine responsiveness and metabolomic changes in the tyrosine/dopamine pathways in striatum and spinal cord.
Spinal cord injury (SCI) leads to opioid-resistant neuropathic pain that is associated with changes in dopamine metabolomics in the spinal cord and striatum of rats. We present evidence that adjuvant targeting of the dopamine system may be a novel pain treatment approach to overcome opioid desensitization and tolerance after SCI.
Stem cells and chronic spinal cord injury: Overview
2022, Diagnosis and Treatment of Spinal Cord Injury
Spinal cord injury (SCI) is a severely disabling condition associated with markedly increased healthcare costs. The pathophysiology underlying SCI involves an acute phase of mechanical trauma to the spinal cord leading to a chronic phase mediated by immune pathways that promote injury exacerbation, spreading, and glial scarring. Given their capability to self-renew and differentiate into various mature cell types, stem cells are posited to be uniquely suited to regenerate the components that are damaged in SCI. Stem cell transplantation into animal models of SCI has demonstrated the ability of stem cells to mature into neurons and glia, engraft into recipient neural circuits, and promote functional motor improvement. Promising findings from these pre-clinical studies have motivated clinical exploration of stem cells for use in human SCI patients. Early clinical trials have demonstrated safety and feasibility of transplantation into patients, and improvements in sensory and motor function have been observed. Larger controlled clinical trials will be necessary to continue to assess the potential therapeutic utility of stem cells in chronic spinal cord injury.
Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain
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Citation Excerpt :
Spinal cord injury (SCI) often leads to neuropathic pain that does not respond well to conventional pain management strategies (Warms et al., 2002; Cruz-Almeida et al., 2005; Masri and Keller, 2012; Felix, 2014; Elman and Borsook, 2016; Gwak et al., 2016).
A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.
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Explore the analgesic effect of brucine, reveal the molecular mechanism of brucine analgesia.
Antinociceptive effects of brucine were assessed in acute and chronic pain mice model. Electrophysiological experiments were used to evaluate the effects of brucine on neuronal activity and sodium channel function.
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Spinal Cord Injury: How Could Acupuncture Help?
2018, JAMS Journal of Acupuncture and Meridian Studies
Spinal cord injury (SCI) is one of the most common causes of death and disability worldwide, and it can result in both permanent disability and serial complications in patients. Research shows that patients with SCI complications are often interested in acupuncture for symptomatic relief. Therefore, the issue of physicians advising their patients regarding the use of acupuncture to alleviate SCI complications becomes pertinent. We review and summarize two types of relevant publications: (1) literature concerning acupuncture for SCI and its complications and (2) underlying mechanisms of acupuncture therapy for SCI. Clinical trials and reviews have suggested that acupuncture effectively manages a range of post-SCI complications, including motor and sensory dysfunction, pain, neurogenic bowel and bladder, pressure ulcers, spasticity, and osteoporosis. The effect of acupuncture on post-SCI orthostatic hypotension and sexual dysfunction remains unclear. Decreased oxidative stress, inhibition of inflammation and neuronal apoptosis, regulation of the expression and activity of endogenous biological mediators, and increased regenerative stem cell production are the possible mechanisms of acupuncture therapy for SCI. Although many limitations have been reported in previous studies, given the evidence for the efficacy of acupuncture, we recommend that physicians should support the use of acupuncture therapy for SCI complications.

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View full text

Combined approaches for the relief of spinal cord injury-induced neuropathic pain

Highlights

Abstract

Introduction

Section snippets

Acupuncture therapy

Psychiatric relief of pain

Acupuncture and reward mechanism

Conclusion

Competing interests

Author’s contribution

Acknowledgements

Neuroscience

Pain

Exp Neurol

Arch Phys Med Rehabil

Ann Emerg Med

Pain

Exp Neurol

Arch Phys Med Rehabil

Pain

Pain

Brain Res

Neurosci Res

Neuroscience

Exp Neurol

J Affect Disord

Neuroimage

Eur J Pain

Pain

J Pain

Neuron

Trends Neurosci

Neurosci Lett

Prog Neurobiol

Neurosci Lett

Neuroscience

Life Sci

Eur J Pain

Neuropharmacology

Behav Brain Res

Pain

Neurosci Lett

Neurosci Lett

Brain Res

Brain Res

Neuroscience

Pain

Mol Pain

J Affect Disord

J Tradit Chin Med

Prog Neurobiol

Bilateral hyperexcitability of thalamic VPL neurons following unilateral spinal injury in rats

J Physiol Sci

Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury

Brain

Gracile neurons contribute to the maintenance of neuropathic pain in peripheral and central neuropathic pain models

J Neurotrauma

Metabotropic glutamate receptors in spinal cord injury: roles in neuroprotection and the development of chronic central pain

J Neurotrauma

Pregabalin for the management of neuropathic pain in spinal cord injury

Pain Manage

Lamotrigine in spinal cord injury pain: a randomized controlled trial

Pain