The Yaksh-model of intrathecal opioid-studies: still exciting four decades later
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In 1976 Tony L. Yaksh and Thomas Rudy published a one-and-half pages paper in Science entitled “Analgesia Mediated by a Direct Spinal Action of Narcotics” [1]. This article opened two very important paths in pain medicine: it was understood that opioids can act on sites in the spinal cord, which had direct clinical applications, and that spinal effects of different classes of analgesics can be studied in a simple and practical model, using awake, behaving rodents with an intrathecal catheter implanted under anesthesia.
This happened 42 years ago. It is worth to remember that opioid receptors were demonstrated to exist in nervous tissue only 3 years earlier [2], and cloned two decades later [3]. Neuraxial – spinal and epidural – administration of opioids was rapidly accepted to clinical use [4], [5]. Interestingly, the first documented case in whom morphine was administered intrathecally, with the local anesthetic cocaine, to treat pain is from 1901, see [6].
Hundreds and hundreds of studies on spinal effects of opioids and a plethora of other possible analgesics acting via different biochemical pathways have been published since the original publication in 1976 [1]. One of the advantages of direct intrathecal administration of experimental compounds is that molecules, which would not reach the spinal cord receptors (e.g. some cannot cross the blood-brain barrier, some are rapidly metabolised after oral or parenteral administration), such as small peptides can be used as research tools.
In the present issue of Scandinavian Journal of Pain, another report on effects of intrathecally administered opioids studied with the Yaksh-model, by the group of Tony L. Yaksh himself, is published [7]. In this paper, the potency and some adverse effects of a series of small opioid peptides (DALDA peptides: DMT-DALDA, dDALc, dDALcn, dDAL-TICP, and dDAL-TIPP) are characterised after intrathecal bolus administration in rats. Special emphasis is put into separating motor adverse effects from actual antinociceptive effects.
These peptides are hydrophilic, like morphine, which may make it possible that they could be used to produce long-lasting effect after single intrathecal bolus dose. As continuous intrathecal administration is somewhat problematic in clinical practice, especially after the adverse effects related to use of very thin spinal catheters that have led to market withdrawals, long analgesia after a single dose would be a highly desirable property of a new spinal analgesic. Obviously, before any clinical application, more research on efficacy and safety is needed.
When the rats were treated with intrathecal morphine for 5 days before administration of DMT-DALDA, the analgesic effect was not reduced [7], as it is for morphine itself as a result of development of tolerance. This “asymmetric tolerance” is interesting, as it could possibly indicate that the peptide has better intrinsic effect compared with morphine.
For the Scandinavian Journal of Pain this paper opens another new area: the Journal has previously published few original papers on the preclinical or basic research on pain. It is nice to begin with a contribution of top class.
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Conflict of interest: The authors declare no conflict of interest.
References
[1] Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1976;192:1357–8.10.1126/science.1273597Search in Google Scholar PubMed
[2] Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:1011–4.10.1126/science.179.4077.1011Search in Google Scholar PubMed
[3] Satoh M, Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther 1995;68:343–64.10.1016/0163-7258(95)02011-XSearch in Google Scholar
[4] Behar M, Magora F, Olshwang D, Davidson JT. Epidural morphine in treatment of pain. The Lancet 1979;1:527–9.10.1016/S0140-6736(79)90947-4Search in Google Scholar PubMed
[5] Bujedo BM, Santos SG, Azpiazu AU. A review of epidural and intrathecal opioids used in the management of postoperative pain. J Opioid Manag 2012;8:177–92.10.5055/jom.2012.0114Search in Google Scholar PubMed
[6] Brill S, Gurman GM, Fisher A. A history of neuraxial administration of local analgesics and opioids. Eur J Anaesthesiol 2003;20:682–9.10.1097/00003643-200309000-00002Search in Google Scholar
[7] Kokubu S, Eddinger KA, Nguyen TM-D, Libertad Huerta-Esquivel L, Yamaguchi S, Schiller PW, Yaksh TL. Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery. Scand J Pain 2019;19:193–206.10.1515/sjpain-2018-0120Search in Google Scholar PubMed
©2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.
Articles in the same Issue
- Frontmatter
- Editorial comment
- The Fear Avoidance Beliefs Questionnaire – the FABQ – for the benefit of another 70 million potential pain patients
- The Yaksh-model of intrathecal opioid-studies: still exciting four decades later
- Pain is common in chronic fatigue syndrome – current knowledge and future perspectives
- Systematic review
- Use of multidomain management strategies by community dwelling adults with chronic pain: evidence from a systematic review
- Clinical pain research
- Topographic mapping of pain sensitivity of the lower back – a comparison of healthy controls and patients with chronic non-specific low back pain
- A prospective study of patients’ pain intensity after cardiac surgery and a qualitative review: effects of examiners’ gender on patient reporting
- Correlations between the active straight leg raise, sleep and somatosensory sensitivity during pregnancy with post-partum lumbopelvic pain: an initial exploration
- Pain is associated with reduced quality of life and functional status in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
- Does validation and alliance during the multimodal investigation affect patients’ acceptance of chronic pain? An experimental single case study
- Translation, cross-cultural adaptation, and psychometric properties of the Hausa version of the Fear-Avoidance Beliefs Questionnaire in patients with low back pain
- Observational study
- Cause-specific mortality of patients with severe chronic pain referred to a multidisciplinary pain clinic: a cohort register-linkage study
- Pain self-efficacy moderates the association between pain and somatization in a community sample
- Pediatric chronic pain and caregiver burden in a national survey
- Psychometric evaluation of the Danish version of a modified Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R-D) for patients hospitalized with acute abdominal pain
- Musculoskeletal pain in multiple body sites and work ability in the general working population: cross-sectional study among 10,000 wage earners
- Prediction of running-induced Achilles tendinopathy with pain sensitivity – a 1-year prospective study
- Original experimental
- Body image is more negative in patients with chronic low back pain than in patients with subacute low back pain and healthy controls
- Identifying pain in children with CHARGE syndrome
- Patients’ perspective of the effectiveness and acceptability of pharmacological and non-pharmacological treatments of fibromyalgia
- Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies
- Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery
- The effects of auditory background noise and virtual reality technology on video game distraction analgesia
- Book review
- Atlas of Common Pain Syndromes, 4th Edition
- Atlas of Ultrasound-Guided Regional Anesthesia, 3rd Edition
- Anaesthesia, Intensive Care and Perioperative Medicine A-Z, 6th Edition
Articles in the same Issue
- Frontmatter
- Editorial comment
- The Fear Avoidance Beliefs Questionnaire – the FABQ – for the benefit of another 70 million potential pain patients
- The Yaksh-model of intrathecal opioid-studies: still exciting four decades later
- Pain is common in chronic fatigue syndrome – current knowledge and future perspectives
- Systematic review
- Use of multidomain management strategies by community dwelling adults with chronic pain: evidence from a systematic review
- Clinical pain research
- Topographic mapping of pain sensitivity of the lower back – a comparison of healthy controls and patients with chronic non-specific low back pain
- A prospective study of patients’ pain intensity after cardiac surgery and a qualitative review: effects of examiners’ gender on patient reporting
- Correlations between the active straight leg raise, sleep and somatosensory sensitivity during pregnancy with post-partum lumbopelvic pain: an initial exploration
- Pain is associated with reduced quality of life and functional status in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
- Does validation and alliance during the multimodal investigation affect patients’ acceptance of chronic pain? An experimental single case study
- Translation, cross-cultural adaptation, and psychometric properties of the Hausa version of the Fear-Avoidance Beliefs Questionnaire in patients with low back pain
- Observational study
- Cause-specific mortality of patients with severe chronic pain referred to a multidisciplinary pain clinic: a cohort register-linkage study
- Pain self-efficacy moderates the association between pain and somatization in a community sample
- Pediatric chronic pain and caregiver burden in a national survey
- Psychometric evaluation of the Danish version of a modified Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R-D) for patients hospitalized with acute abdominal pain
- Musculoskeletal pain in multiple body sites and work ability in the general working population: cross-sectional study among 10,000 wage earners
- Prediction of running-induced Achilles tendinopathy with pain sensitivity – a 1-year prospective study
- Original experimental
- Body image is more negative in patients with chronic low back pain than in patients with subacute low back pain and healthy controls
- Identifying pain in children with CHARGE syndrome
- Patients’ perspective of the effectiveness and acceptability of pharmacological and non-pharmacological treatments of fibromyalgia
- Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies
- Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery
- The effects of auditory background noise and virtual reality technology on video game distraction analgesia
- Book review
- Atlas of Common Pain Syndromes, 4th Edition
- Atlas of Ultrasound-Guided Regional Anesthesia, 3rd Edition
- Anaesthesia, Intensive Care and Perioperative Medicine A-Z, 6th Edition
