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Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment.

ABSTRACT: Previously, we reported that H-2',6'-dimethyltyrosine [Dmt(1)]-d-Arg-Phe-Lys-NH(2) (DALDA), an analogue of the naturally occurring opioid peptide dermorphin, is a highly potent and selective mu receptor agonist with low cross-tolerance to morphine. In the present study, we investigated the effect of treating mice chronically with [Dmt(1)]DALDA. The AD(50) of [Dmt(1)]DALDA (s.c.) increased eight-fold in animals given this drug chronically; in contrast, the AD(50) increased two-fold in mice chronically treated with morphine. The AD(50) of morphine (s.c.) in these [Dmt(1)]DALDA-treated animals was increased more than 120 times, while that of the more selective mu agonist [d-Ala(2)-MePhe(4)-Gly-ol(5)]enkephalin (DAMGO) given intrathecally was increased more than 240 times. However, the AD(50) of DAMGO given intracerebroventricularly was essentially the same in animals treated chronically with [Dmt(1)]DALDA as in naive animals. The dose of naloxone required to precipitate withdrawal in [Dmt(1)]DALDA-treated animals was 20 times lower than that in morphine-tolerant animals. Using real-time quantitative PCR, we found that expression of the mu opioid receptor, delta opioid receptor, preproenkephalin and preprodynorphin genes was upregulated in the brain by [Dmt(1)]DALDA treatment. No significant changes in expression of opioid receptor or opioid peptide genes were detected in the spinal cord of [Dmt(1)]DALDA-treated mice, nor in the brain or spinal cord of morphine-treated mice. We conclude that a high degree of tolerance to [Dmt(1)]DALDA develops in the spinal cord but not brain, and cannot be accounted for by changes in expression of opioid receptors or opioid peptides in these tissues.

SUBMITTER: Ben Y

PROVIDER: S-EPMC1575960 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment.

Ben Yong Y Smith Andrew P AP Schiller Peter W PW Lee Nancy M NM

British journal of pharmacology 20041122 8

Previously, we reported that H-2',6'-dimethyltyrosine [Dmt(1)]-d-Arg-Phe-Lys-NH(2) (DALDA), an analogue of the naturally occurring opioid peptide dermorphin, is a highly potent and selective mu receptor agonist with low cross-tolerance to morphine. In the present study, we investigated the effect of treating mice chronically with [Dmt(1)]DALDA. The AD(50) of [Dmt(1)]DALDA (s.c.) increased eight-fold in animals given this drug chronically; in contrast, the AD(50) increased two-fold in mice chroni ...[more]

PMID: 15557286

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Project description:With emerging applications of spinal cord electrical stimulation in restoring autonomic and motor function after spinal cord injury, understanding the neuroanatomical substrates of the human spinal cord after spinal cord injury using neuroimaging techniques can play a critical role in optimizing the outcomes of these stimulation-based interventions. In this study, we have introduced a neuroimaging acquisition and analysis protocol of the spinal cord in order to identify: (i) spinal cord levels at the lumbosacral enlargement using nerve root tracing; (ii) variability in the neuroanatomical characteristics of the spinal cord among individuals; (iii) location of the epidural stimulation paddle electrode and contacts with respect to the spinal cord levels at lumbosacral enlargement; and (iv) the links between the anatomical levels of stimulation and the corresponding neurophysiological motor responses. Twelve individuals with chronic, motor complete spinal cord injury implanted with a spinal cord epidural stimulator were included in the study (age: 34 ± 10.9 years, sex: 10 males, 2 females, time since injury: 8.2 ± 9.9 years, American Spinal Injury Association Impairment Scale: 6 A, 6 B). High-resolution MRI scans of the spinal cord were recorded pre-implant. An analysis of neuroanatomical substrates indicates that the length of the spinal column and spinal cord, location of the conus tip and the relationship between the spinal cord levels and vertebral levels, particularly at the lumbosacral enlargement, are variable across individuals. There is no statistically significant correlation between the length of the spinal column and the length of the spinal cord. The percentage of volumetric coverage of the lumbosacral spinal cord by the epidural stimulation paddle electrode ranges from 33.4 to 90.4% across participants. The location of the spinal cord levels with respect to the electrode contacts varies across individuals and impacts the recruitment patterns of neurophysiological responses. Finally, MRI-based spinal cord modelling can be used as a guide for the prediction and preplanning of optimum epidural stimulation paddle placement prior to the implant surgery to ensure maximizing functional outcomes. These findings highlight the crucial role that the neuroanatomical characteristics of the spinal cord specific to each individual play in achieving maximum functional benefits with spinal cord electrical stimulation.

Project description:ObjectivesSpinal cord stimulation (SCS) has emerged as an appropriate modality of treatment for intractable chronic pain. The present study examines variations in SCS trial-to-permanent conversion rates based on provider types performing the procedure.Materials and methodsWe designed a large, retrospective analysis using the Truven MarketScan data base analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007-2012. Patients were categorized based on provider type performing the implantation including anesthesiologists, neurosurgeons, orthopedic surgeons, and physical medicine and rehabilitation (PM&R). Univariate and multivariate models identified factors associated with successful conversion.ResultsA total of 7667 unique instances of SCS implants were identified across five providers. Overall, 4842 (63.2%) of those receiving trials underwent permanent SCS system implantation. Anesthesiology performed the majority of implants (62.8%), followed by neurosurgery (22.0%), orthopedic surgery (10.2%), and PM&R (5.3%). Compared to anesthesiologists, both neurosurgeons (OR 10.99, 95% CI [9.11, 13.25]; p < 0.001) and orthopedic surgeons (OR 4.64, 95% CI [3.81, 5.65]; p < 0.001) had significantly higher conversion rates, while PM&R (OR 0.71, 95% CI [0.58, 0.87]; p = 0.001) had significantly lower. Percutaneous implants comprised 5473 (71.4%) of all implants. Neurosurgeons and orthopedic surgeons performed a significantly greater number of paddle implants among the different providers (p < 0.0001). Explant rates were similar across all cohorts analyzed (average 11.6%; p = 0.546).ConclusionsIn this nationwide analysis, our results suggest that over a recent five-year period, conversion rates are highest when SCS trials are performed by neurosurgeons and orthopedic surgeons. The study has important implications for establishing uniform guidelines for training, patient selection, and education of physicians across multiple disciplines.

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Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment.

Publications

Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment.

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