Investigation on Cerebrospinal Fluid Opioids and Neurotransmitters Related to Spinal Cord Stimulation

Tonelli, Laura; Setti, T.; Falasca, Angelo; Martignoni, E.; Torcia, E.; Calcaterra, F.M.; Merli, G; Facchinetti, Fabio

doi:10.1159/000099977

Cited by 27 publications

(33 citation statements)

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“…The levels of dopamine and adrenaline were unaffected in this study (but were elevated in plasma). There are also some studies with conflicting results published [8,19,27,56].…”

Section: Discussionmentioning

confidence: 99%

“…It should also be remembered that SCS is often effective in pain syndromes which are considered relatively in sensitive to opioids. Only in one study by Tonelli et al [19] were there some patients displaying a release of (5-Iipotropin and [3-endorphin in lumbar CSF following SCS. There are also several investigators who have been unable to find any increase in endogenous opioids in CSF after SCS [20].…”

Section: Introductionmentioning

confidence: 99%

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Release of Neurotransmitters in the CNS by Spinal Cord Stimulation: Survey of Present State of Knowledge and Recent Experimental Studies

Linderoth

Co²,

Gunasekera³

et al. 1993

Stereotact Funct Neurosurg

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Electric Stimulation applied to the posterior surface of the spinal cord (SCS) is an established treatment in certain chronic pain syndromes resistant to con-ventional therapeutic procedures. Despite the clinical value of SCS, the mechanisms behind the efficacy of the method are largely unknown. Several neurotransmitters in the CNS (e.g. Opioids, serotonin, noradrenaline, substance P, GABA), have been pro-posed to be involved in the pain-alleviating effect of SCS. However, as yet there is no evidence that these would be involved in the beneficial effects of SCS. We have studied neurotransmitter release, using microdialysis techniques, in the spinal dorsal horn and the periaqueductal grey substance (PAG) of the rat and the cat, induced by SCS applied with current parameters equivalent to those used clinically in man. Up to now dialysates have been assayed for GABA, serotonin and substance P with highly sensitive methods. Three groups of studies have been carried out: (1) dorsal horn microdialysis in rats under halothane anesthesia during acute SCS; (2) dorsal horn microdialysis in cats under barbiturate anesthesia or following decerebration, and (3) PAG microdialysis in awake, unrestrained rats with chronic SCS. In the dorsal horn studies, microdialysis probes of different sizes were implanted in the lower lumbar dorsal horns. In the PAG studies, rats had guide cannulas for microdialysis stereotactically inserted into the PAG. SCS was applied at a low thoracic level with 50 or 100 Hz; 0.2 ms and an intensity amounting to ²/₃ of the motor threshold. The microdialysis probes were perfused with modified Ringer''s solution. Fractions of the dialysate were collected at various intervals. GABA and serotonin were assayed by reverse-phase HPLC, while substance P was investigated using a highly sensitive radioimmunoassay. SCS induced a significant release of GABA in the dorsal horn, most marked in the fraction following the stimulation period. In the rats with PAG microdialysis, the GABA level decreased significantly following two stimulation periods, although transitional increases during SCS were noted in some animals. In the decerebrated cat, a significant release of serotonin in the dorsal horn was obtained with SCS, while the levels of the metabolite 5-HIAA were little influenced by stimulation. On the contrary, in the decerebrated preparation there was no release of substance P in the dorsal horn with SCS, although in the intact cat under barbiturate anesthesia a significant release was induced. the observation paramters'' is consistent with the view that these substances may be involved in hibition of nociceptive transmission. Furthermore, there are hypersensitivity of wide dynamic symptom is often successfully treated by SCS. The putative role of substance P in SCS is more vague. There are descending pathways with a hypothetical inhibitory function whre substance P and serotonin coexist. The present observations might indicate that substance P is also involved in the beneficial effects of SCS ...

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“…The levels of dopamine and adrenaline were unaffected in this study (but were elevated in plasma). There are also some studies with conflicting results published [8,19,27,56].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Release of Neurotransmitters in the CNS by Spinal Cord Stimulation: Survey of Present State of Knowledge and Recent Experimental Studies

Linderoth

Co²,

Gunasekera³

et al. 1993

Stereotact Funct Neurosurg

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“…Also, in 1988, Tonelli et al found low CSF-BE in patients scheduled for Spinal Cord Stimulation (SCS), compared to historic controls [238]. As a contrast, in 1988, Vaeroy et al found normal levels of CSF-BE in fibromyalgia syndrome patients [244].…”

Section: Neuropeptidesmentioning

confidence: 99%

“…Concerning CSF-BE, longitudinal studies before and after an invasive intervention have yielded inconclusive results, and/or results that are difficult to interpret due to the nature of the intervention [87,238]. In one of these studies [87], mean CSF-BE decreased by 56% in 9 patients 12-17 days after successful treatment with Dorsal Root Entry Zone Lesions.…”

Section: The Temporal Variation Of Csf-bementioning

confidence: 99%

“…Biomarker CSF candidates in earlier studies have included Cystatin C [75,146], nociceptin [35,195], and different neurotrophins [40,143]. SP and BE are also classical candidates, and on the basis of Paper III and other studies [3,4,138,208,238,244,245], one might perhaps hypothesize that peripheral neuropathic pain and fibromyalgia are characterized by different combined patterns of CSF-BE and CSF-SP: the former would be associated with a tendency to low CSF-BE and normal/low CSF-SP, whereas the latter would be associated with a tendency to normal CSF-BE and high CSF-SP. Hence, CSF-BE and CSF-SP may perhaps in the future be part of a panel of proteins used to discriminate between different pain conditions.…”

Section: Candidate Proteins Vs Proteomicsmentioning

confidence: 99%

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The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

Bäckryd¹

2015

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The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain. In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question. In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor. In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses

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Spinal cord stimulation reduces hypersensitivity through activation of opioid receptors in a frequency‐dependent manner

Sato

King

Johanek

et al. 2012

European Journal of Pain

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Investigation on Cerebrospinal Fluid Opioids and Neurotransmitters Related to Spinal Cord Stimulation

Cited by 27 publications

References 0 publications

Release of Neurotransmitters in the CNS by Spinal Cord Stimulation: Survey of Present State of Knowledge and Recent Experimental Studies

Release of Neurotransmitters in the CNS by Spinal Cord Stimulation: Survey of Present State of Knowledge and Recent Experimental Studies

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

Spinal cord stimulation reduces hypersensitivity through activation of opioid receptors in a frequency‐dependent manner

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