• Locus coeruleus;
  • receptors;
  • opioid;
  • phosphoprotein phosphatase;
  • drug tolerance
  • 1
    Acute homologous desensitization of μ-opioid receptor-induced currents was pharmacologically characterized in locus coeruleus (LC) neurones by use of intracellular and whole cell recording in superfuised brain slices.
  • 2
    Following desensitization of opioid receptors by perfusion with a high concentration of [Met5] enkephalin (ME) for 5 min, there was a reduction in the maximum response and a rightward shift of the concentration - response curves for ME, [D-Ala2, N-MePhe4, Gly - ol] enkephalin (DAMGO) and nor-morphine.
  • 3
    By simultaneously fitting the operational model to the paired pre- and post-desensitization concentration-response data for each agonist, estimates of the level of desensitization were obtained. The values obtained for the three agonists (between 88% and 96%) were similar and did not vary according to the efficacy of the agonist used.
  • 4
    Use of whole cell patch recording techniques caused a slow rundown in the amplitude of ME currents (approx. 40% reduction over 60 min) but did not greatly affect the expression of acute desensitization of opioid currents.
  • 5
    When included in the patch recording solution, the phosphatase inhibitors, microcystin (50 nM-4 μm) and okadaic acid (1 μm) had no effect on the induction of desensitization or the normal ability of opioid or α2-adrenoceptors to produce currents. Microcystin decreased the rate of recovery of the ME (300 nM) currents following desensitization; however, okadaic acid had little effect on the rate of recovery from desensitization.
  • 6
    Strong calcium buffering with BAPTA (10–20 mM) had no effect on desensitization or the recovery from desensitization.
  • 7
    These results suggest that acute homologous desensitization of μ-opioid receptors in LC neurones entails a rapid loss of responsiveness that involves a majority of the receptor population. The mechanism by which desensitization is reversed may involve a non-calcium-dependent protein phosphatase but the processess that cause desensitization remain unclear.