Cholecystokinin and morphine analgesia: variations on a theme

Stanfa, Louise C.; Dickenson, Anthony H.; Xu, Xiao‐Jun; Wiesenfeld‐Hallin, Zsuzsanna

doi:10.1016/0165-6147(94)90279-8

Cited by 143 publications

(52 citation statements)

References 21 publications

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“…There is considerable evidence that while CCK modulates the antinociceptive activity of opioids, the opioids in turn promote CCK release in the brain and the spinal cord, apparently keeping a harmonious balance between endogenous pronociceptive and antinociceptive systems [166,167,[171][172][173] . Microdialysis techniques performed in vivo demonstrated that acute systemic and spinal morphine administration increased CSF levels of CCK in the spinal cord [172,174] .…”

Section: Role Of Cck As An Endogenous Pronociceptive (Or 'Anti-opioidmentioning

confidence: 99%

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

et al. 2005

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Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. ‘analgesic tolerance’. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.

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Section: Role Of Cck As An Endogenous Pronociceptive (Or 'Anti-opioidmentioning

confidence: 99%

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

et al. 2005

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“…88 Alternatively, antagonists of the CCK receptor may enhance the analgesic action of opioids. 89,90 It has been shown that NMDA receptor activation results in formation of nitric oxide (NO). Inhibitors of NO synthetase, the enzyme responsible for synthesis of NO, are antinociceptive, suggesting a possible future role in pain medicine.…”

Section: Nmda Receptor Antagonistsmentioning

confidence: 99%

Preemptive analgesia I: physiological pathways and pharmacological modalities

Kelly

Ahmad

Brull

2001

Can J Anesth/J Can Anesth

259

181

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P Pu ur rp po os se e: : This two-part review summarizes the current knowledge of physiological mechanisms, pharmacological modalities and controversial issues surrounding preemptive analgesia.S So ou ur rc ce e: : Articles from 1966 to present were obtained from the MEDLINE databases. Search terms included: analgesia, preemptive; neurotransmitters; pain, postoperative; hyperalgesia; sensitization, central nervous system; pathways, nociception; anesthetic techniques; analgesics, agents.P Pr ri in nc ci ip pa al l f fi in nd di in ng gs s: : The physiological basis of preemptive analgesia is complex and involves modification of the pain pathways. The pharmacological modalities available may modify the physiological responses at various levels. Effective preemptive analgesic techniques require multi-modal interception of nociceptive input, increasing threshold for nociception, and blocking or decreasing nociceptor receptor activation. Although the literature is controversial regarding the effectiveness of preemptive analgesia, some general recommendations can be helpful in guiding clinical care. Regional anesthesia induced prior to surgical trauma and continued well into the postoperative period is effective in attenuating peripheral and central sensitization. Pharmacologic agents such as NSAIDs (non-steroidal anti-inflammatory drugs) opioids, and NMDA (Nmethyl-D-aspartate) -and alpha-2-receptor antagonists, especially when used in combination, act synergistically to decrease postoperative pain.C Co on nc cl lu us si io on n: : The variable patient characteristics and timing of preemptive analgesia in relation to surgical noxious input requires individualization of the technique(s) chosen. Multi-modal analgesic techniques appear most effective.Objectif : La présente revue, en deux parties, résume les connaissances actuelles sur les mécanismes physiologiques et les modalités pharmacologiques de lanalgésie préventive ainsi que sur les questions controversées qui lentourent.Sources : Des articles, de 1966 à aujourdhui, obtenus à partir des bases de données MEDLINE. Les termes de la recherche compren-

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“…While mechanisms of neuropathic pain are still being elucidated, emerging studies indicate the involvement of neuroplasticity in which significant increased expression of neuromodulators and neurotransmitters in the central nervous system such as cholecystokinin (CCK) occurs [17,46,47,49,50]. CCK-8 is a linear octapeptide found in the periphery as a hormone and in the central nervous system (CNS) as a neurotransmitter where it is commonly associated with satiety and anxiety, respectively [34,35].…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

et al. 2008

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Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[DCys-Gly-Trp-Cys]-Asp-Phe-NH 2 ) showed potent binding and agonist activities at δ and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

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Cholecystokinin and morphine analgesia: variations on a theme

Cited by 143 publications

References 21 publications

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Preemptive analgesia I: physiological pathways and pharmacological modalities

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

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