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Chronic escapable footshock causes a reduced response to morphine in rats as assessed by local cerebral metabolic
B D Gescuk1, S Lang, C Kornetsky
1Laboratory of Behavioral Pharmacology, Boston University School of Medicine, MA 02118, USA.
Abstract:
The 2-deoxy-D-[14C]glucose (2-DG) method was used to examine the effects of morphine sulfate (MS) on local cerebral metabolic rates for glucose (LCMRglu) in male F-344 rats required to turn a wheel manipulandum in order to escape from nociceptive footshock. This nociceptive stimulus was identical with that utilized in a previous 2-DG study from this laboratory [15] except that animals were exposed to 15 daily 30 min sessions of footshock prior to the 2-DG testing day rather than a single footshock exposure. This allows a direct comparison of the effects of morphine in chronic and acute pain. Unlike the acute footshock study, morphine in chronic footshock rats did not have a significant effect compared with chronic footshock alone in any of the 73 measured brain structures, including limbic and midline thalamic structures previously shown to be important in morphine-induced analgesia during acute pain [15]. Whereas 93% of measured cerebral structures showed decreases in LCMRglu following morphine administration in the acute footshock rats, morphine given to chronic footshock rats caused decreases in only 56% of the structures as compared with chronic footshock plus saline. It is hypothesized that these differential effects of morphine are due in part to a habituation to the chronic stressor such that chronic footshock rats are less stressed than acute footshock rats. Additionally, it is suggested that chronic exposure to pain produces a constant elevation of opioid peptides leading to opioid receptor downregulation and consequently morphine tolerance. These results demonstrate that, even in the presence of the same nociceptive stimulus, morphine can have widely disparate effects on brain metabolism if there are differences in the pain history of the animal.
Insights
Morphine sulfate (MS) effects on brain glucose metabolism differ significantly between acute and chronic pain. Chronic pain exposure leads to morphine tolerance, reducing its impact on cerebral metabolic rates for glucose (LCMRglu).
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- The 2-deoxy-D-[14C]glucose (2-DG) method measures local cerebral metabolic rates for glucose (LCMRglu).
- Morphine sulfate (MS) is a common analgesic.
- Previous studies indicated MS affects brain metabolism during acute pain.
Purpose of the Study:
- To investigate the effects of MS on LCMRglu in rats experiencing chronic pain.
- To compare MS effects in chronic pain versus acute pain models.
- To explore potential mechanisms for altered MS efficacy in chronic pain.
Main Methods:
- Male F-344 rats were subjected to 15 daily sessions of nociceptive footshock (chronic pain model).
- The 2-deoxy-D-[14C]glucose (2-DG) method was used to measure LCMRglu.
- Effects of morphine sulfate were compared between chronic footshock, acute footshock, and control groups.
Main Results:
- Morphine sulfate did not significantly alter LCMRglu in any of the 73 brain structures examined in the chronic pain group.
- In contrast, acute pain exposure showed decreased LCMRglu in 93% of measured brain structures following MS administration.
- Chronic pain rats exhibited decreased LCMRglu in only 56% of structures compared to chronic footshock plus saline.
Conclusions:
- Habituation to chronic stress and potential opioid receptor downregulation may contribute to reduced MS efficacy in chronic pain.
- Chronic pain exposure can lead to morphine tolerance, altering brain metabolic responses to the drug.
- An animal's pain history significantly influences the effects of morphine on brain metabolism, even with identical nociceptive stimuli.