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Cholecystokinin/opioid interactions
Z Wiesenfeld-Hallin1, G de Araúja Lucas, P Alster
1Karolinska Institutet, Department of Medical Laboratory Sciences and Technology, Division of Clinical Neurophysiology, Huddinge University Hospital, S-141 86, Huddinge, Sweden. zsuzsanna.wiesenfeld-hallin@neurophys.hs.sll.se
Abstract:
Cholecystokinin (CCK) acts as an anti-opioid peptide. The mechanisms of CCK-opioid interaction under normal and pathological conditions were examined with various techniques. Nerve injury induces upregulation of CCK mRNA and CCK2 receptors in sensory neurons. The involvement of CCK in spinal nociception in normal and axotomized rats was examined. The CCK2 receptor antagonist CI-988 did not reduce spinal hyperexcitability following repetitive C-fiber stimulation in normal or axotomized rats, suggesting that CCK is probably not released from injured primary afferents. With in vivo microdialysis intravenous (i.v.) or intrathecal (i.t.) morphine increased the extracellular level of CCK in the dorsal horn in a naloxone reversible manner. Morphine also released CCK after axotomy, but not during carrageenan-induced inflammation. In contrast, K(+)-stimulation failed to increase extracellular levels of CCK in axotomized rats, but did so in inflamed rats. Double-coloured immunofluorescence technique revealed partial co-localization between CCK-like immunoreactivity (LI) and mu-opioid receptor (MOR)-LI in superficial dorsal horn neurons. The presence of MOR in CCK containing neurons suggests a possible direct influence of opioids on CCK release in the spinal cord. Axotomy, but not inflammation, induced a moderate decrease in CCK- and MOR-LI in the dorsal horn. I.v. morphine further temporarily reduced CCK- and MOR-LIs in axotomized, but not in normal or inflamed, rats. While the effect of morphine on CCK-LI can be interpreted as the result of increased CCK release, the effect on MOR-LI may be related to changes in the microenvironment of the dorsal horn induced by nerve injury.
Insights
Cholecystokinin (CCK) interacts with opioids in pain pathways. Nerve injury alters CCK and opioid receptor levels, but CCK may not be directly involved in spinal hyperexcitability after nerve injury.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Cholecystokinin (CCK) acts as an anti-opioid peptide, modulating pain perception.
- Nerve injury is known to upregulate CCK and its receptors in sensory neurons.
Purpose of the Study:
- To investigate the interaction between CCK and opioid systems in spinal nociception.
- To examine the role of CCK in normal and pathological pain states, specifically after nerve injury and inflammation.
Main Methods:
- In vivo microdialysis to measure extracellular CCK levels in the dorsal horn.
- CCK2 receptor antagonist (CI-988) administration.
- Double-colored immunofluorescence for CCK and mu-opioid receptor (MOR) co-localization.
- Assessment of CCK and MOR immunoreactivity (LI) in dorsal horn neurons.
Main Results:
- CCK2 receptor antagonism did not affect spinal hyperexcitability, suggesting CCK is not released from injured primary afferents.
- Intravenous or intrathecal morphine increased extracellular CCK in the dorsal horn in a naloxone-reversible manner.
- Morphine released CCK after axotomy but not during inflammation; K(+)-stimulation released CCK during inflammation but not after axotomy.
- Partial co-localization of CCK and MOR was observed in dorsal horn neurons.
- Axotomy, but not inflammation, decreased CCK and MOR immunoreactivity; morphine further reduced these in axotomized rats.
Conclusions:
- CCK may not be directly involved in spinal hyperexcitability following nerve injury.
- Opioids can modulate CCK release in the spinal cord, potentially via direct influence on CCK-containing neurons.
- Nerve injury and opioid administration induce complex changes in CCK and MOR expression and release in the spinal cord.