Different profile of electrocortical power spectrum changes after micro‐infusion into the locus coeruleus of selective agonists at various opioid receptor subtypes in rats
Authors: Bagetta G. , DE Sarro G.B. , Sakurada S. , Rispoli V. , Nisticò G. 
Published: July 2012

The effects of various opioid receptor agonists given directly by means of a chronically implanted cannula into the locus coeruleus (LC) on behaviour and ECoG activity, continuously analysed, and quantified as total power spectrum (0–16 Hz) and in preselected frequency bands (0–3; 3–6; 6–9; 9–12 and 12–16 Hz), were studied in rats.

Dermorphin (0.05, 0.5, 1, 2 and 5 pmol) and Tyr‐d‐Ala‐Gly‐N‐Me‐Phe‐Gly‐ol (DAMGO; 1, 10, 30, 100 pmol and 1 nmol), two typical μ‐receptor agonists, applied unilaterally or bilaterally directly into the LC, produced a typical dose‐dependent ECoG synchronization with a significant increase in total power spectrum as well as in the lower frequency bands. Dermorphin was found to be approximately 30 times more powerful than DAMGO in producing similar quantitative ECoG changes.

d‐Ala‐d‐Leu‐Thr‐Gly‐Gly‐Phe‐Leu (DADLE; 1, 10, 50 and 100 pmol), a selective δ‐receptor agonist, micro‐infused into the LC produced dose‐dependent behavioural soporific effects and ECoG increase in total power spectrum as well as in 3–6, 6–9, 9–12 Hz frequency bands. In comparison to dermorphin, the ECoG power spectrum effects of DADLE were 10 fold less potent, whereas in comparison to DAMGO it was approximately 3 times more potent. A lower dose (0.1 pmol) was ineffective in changing behaviour and ECoG power spectrum.

The microinfusion into the LC of U 50, 488H, a selective κ‐opioid receptor agonist, (0.25, 1, 2.5, 5 and 10 pmol) produced a typical pattern characterized by a first short‐lasting (3–25 min) phase of behavioural arousal and ECoG desynchronization, followed by a longer lasting (20–130 min according to the dose) phase of behavioural sleep and ECoG synchronization. A lower dose (0.1 pmol) was ineffective in changing behaviour and ECoG power spectrum.

Dextromethorphan and ketamine, two selective agonists at σ‐receptors given into the LC (1, 5 and 10 pmol) induce behavioural arousal, increase in locomotor activity and an intense pattern of stereotyped movements. However, by increasing the dose of ketamine (50 and 100 pmol), marked sedation, postural changes and an increase in low frequency ECoG bands, sometimes associated with high amplitude fast frequency potentials, were observed.

Naloxone applied directly into the LC (1 and 2 pmol 15 min before) was able to prevent the behavioural and ECoG effects induced by dermorphin, DAMGO and DADLE. Higher doses of naloxone (10 pmol into the LC) were however, required to antagonize the behavioural and ECoG soporific effects induced by the κ‐receptor agonist U 50,488H. In contrast, naloxone (10 pmol into the LC) was unable to prevent or reduce the behavioural and ECoG effects induced by subsequent administration into the same site of dextromethorphan and ketamine.

In conclusion, the present experiments confirm that behavioural and ECoG effects elicited following stimulation of μ‐, δ‐, κ‐ and σ‐opioid receptors located in the LC are quite different. Activation of μ‐, δ‐and κ‐receptors induced sedative effects whereas dextromethorphan and ketamine, two σ‐receptor agonists, induced behavioural arousal and ECoG desynchronization. In addition, the present results strongly support the crucial role played by opioid mechanisms, in the locus coeruleus, in the mediation of the soporific effects of drugs acting as agonists at opioid receptors.