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Inhibition of Ca2+ currents by a mu-opioid in a defined subset of rat sensory neurons
1Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110.
Abstract:
Activation of the endogenous opioid system can suppress pain without affecting other sensations, but the cellular mechanism of this selectivity is unclear. The analgesia might be due to inhibitory synapses arranged only on neurons whose activity leads to pain sensations. Alternatively, opioids might be released broadly, with neurons involved in pain sensation being especially sensitive. Therefore, we asked whether different subsets of rat dorsal root ganglion (DRG) sensory neurons vary in their sensitivity to opioids. Dissociated neurons were subdivided according to the spinal laminae to which they likely had projected, and whether they had innervated muscle. Using the patch-clamp method, we measured the inhibition of Ca2+ current by DAGO (Tyr-D-Ala-Gly-MePhe-Gly-ol), a peptide that selectively activates the mu (morphine) receptor. We also investigated the presence of different types of Ca2+ channels. In DRG neurons chosen at random, Ca2+ currents were inhibited by DAGO to widely varying degrees, with an average inhibition of 38%. Ca2+ currents in neurons in a subset that projects to laminae I and II had a lower average inhibition, and unlike the randomly selected cells, the responses were predictable and tightly distributed about the mean. This indicates that the variability of opioid sensitivity among DRG neurons reflects the presence of different subsets of cells. Since neurons projecting to laminae I and II, the projection site of nociceptive neurons, did not show high opioid sensitivity, there is no evidence that nociceptive neurons have stronger responses to opioids. But a firm conclusion is impossible because projection site does not strictly define sensory modality.
Insights
Opioid pain relief selectivity is not fully understood. This study found varying opioid sensitivity in rat sensory neurons, suggesting different cell types contribute to this effect.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- The endogenous opioid system modulates pain perception.
- The cellular mechanisms underlying opioid-induced pain selectivity remain unclear.
- Opioid analgesia may involve selective inhibition of pain-sensing neurons or differential sensitivity of these neurons.
Purpose of the Study:
- To investigate variations in opioid sensitivity among different subsets of rat dorsal root ganglion (DRG) sensory neurons.
- To determine if specific neuronal populations exhibit differential responses to opioid receptor activation.
Main Methods:
- Dissociated rat DRG neurons were classified based on spinal cord projection targets (laminae) and peripheral innervation (muscle).
- Patch-clamp electrophysiology was used to measure the inhibition of calcium (Ca2+) currents by DAGO, a mu-opioid receptor agonist.
- Calcium channel subtypes were also investigated.
Main Results:
- A wide range of DAGO-induced Ca2+ current inhibition (average 38%) was observed in randomly selected DRG neurons.
- Neurons projecting to spinal laminae I and II showed lower and more consistent inhibition by DAGO compared to randomly selected neurons.
- This variability suggests distinct subsets of DRG neurons possess different opioid sensitivities.
Conclusions:
- The observed variability in opioid sensitivity among DRG neurons indicates the presence of functionally distinct neuronal subsets.
- Contrary to some hypotheses, neurons projecting to laminae I and II (associated with nociception) did not display heightened opioid sensitivity.
- Further research is needed as projection site alone may not definitively identify sensory modality and opioid response.