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mu-Opioid peptides inhibit thalamic neurons
1Department of Physiology, University Medical Center, 1211 Geneva 4, Switzerland.
Abstract:
Opioidergic inhibition of neurons in the centrolateral nucleus of the thalamus was investigated using an in vitro thalamic slice preparation from young rats. The mu-opioid receptor agonist D-Ala2,N-Me-Phe4,glycinol5-enkephalin (DAMGO) evoked a hyperpolarization and decrease in input resistance that was reversible, concentration-dependent, and persisted in the presence of tetrodotoxin. Application of the specific mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide blocked this response. The respective delta- and kappa-opioid receptor agonists, (D-Pen2, D-Pen5)-enkephalin and (+/-)-trans-U-50488 methanesulfonate had no effect. Voltage-clamp experiments showed that DAMGO activated an inwardly rectifying potassium conductance (GKIR) characterized by rectification at hyperpolarized potentials that increased in elevated extracellular potassium concentrations, a complete block by Ba2+ (1 mM), and a voltage-dependent block by Cs+. The extent of mu-opioid inhibition in other thalamic nuclei was then investigated. Widespread inhibition similar to that seen in the centrolateral nucleus was observed in a number of sensory, motor, intralaminar, and midline nuclei. Our results suggest that the net action of opioids would depend on their source: exogenous (systemically administered) opiates inhibiting the entire thalamus and favoring the shift of cell firing from tonic to bursting mode; and endogenously released opioids acting on specific thalamic nuclei, their release depending on the origin of the presynaptic input.
Insights
Opioids inhibit thalamic neurons via mu-opioid receptors, activating potassium channels. This widespread inhibition affects sensory and motor functions, with effects varying based on opioid source.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- The thalamus plays a crucial role in relaying sensory, motor, and cognitive information.
- Opioidergic systems modulate neuronal activity, but their specific effects on thalamic nuclei are not fully understood.
Purpose of the Study:
- To investigate the effects of mu-opioid receptor activation on neurons in the centrolateral nucleus of the thalamus.
- To characterize the ionic mechanisms underlying opioid-induced inhibition.
- To examine the distribution of mu-opioid receptor-mediated inhibition across different thalamic nuclei.
Main Methods:
- In vitro electrophysiology using rat thalamic slices.
- Application of specific mu-opioid receptor agonists (DAMGO) and antagonists.
- Voltage-clamp recordings to identify activated conductances.
- Assessment of opioid effects in various thalamic nuclei.
Main Results:
- Mu-opioid receptor activation by DAMGO caused hyperpolarization and decreased input resistance in centrolateral nucleus neurons.
- This effect was mediated by the activation of an inwardly rectifying potassium conductance (GKIR).
- Widespread mu-opioid inhibition was observed in sensory, motor, intralaminar, and midline thalamic nuclei.
Conclusions:
- Mu-opioid receptors are widely distributed in the thalamus and mediate neuronal inhibition.
- Exogenous opioids broadly inhibit the thalamus, potentially altering cell firing modes.
- Endogenous opioids may exert more specific effects depending on their release source and target nuclei.