Abstract
In morphine tolerance a key question that remains to be answered is whether μ-opioid receptor (MOPr) desensitization contributes to morphine tolerance, and if so by what cellular mechanisms. Here we demonstrate that MOPr desensitization can be observed in single rat brainstem locus coeruleus (LC) neurons following either prolonged (> 4 h) exposure to morphine in vitro or following treatment of animals with morphine in vivo for 3 days. Analysis of receptor function by an operational model indicated that with either treatment morphine could induce a profound degree (70–80%) of loss of receptor function. Ongoing PKC activity in the MOPr-expressing neurons themselves, primarily by PKCα, was required to maintain morphine-induced MOPr desensitization, because exposure to PKC inhibitors for only the last 30–50 min of exposure to morphine reduced the MOPr desensitization that was induced both in vitro and in vivo. The presence of morphine was also required for maintenance of desensitization, as washout of morphine for > 2 h reversed MOPr desensitization. MOPr desensitization was homologous, as there was no change in α2-adrenoceptor or ORL1 receptor function. These results demonstrate that prolonged morphine treatment induces extensive homologous desensitization of MOPrs in mature neurons, that this desensitization has a significant PKC-dependent component and that this desensitization underlies the maintenance of morphine tolerance.
Highlights
The analgesic, respiratory depressant and rewarding effects of morphine occur through activation of l-opioid receptors (MOPrs; Matthes et al, 1996; Romberg et al, 2003)
To determine the extent of MOPr desensitization resulting from prolonged morphine exposure, we developed a protocol that would enable us to assess the extent of receptor desensitization following prolonged morphine exposure without washing out the morphine as washout of morphine would induce withdrawal and initiate reversal of any desensitization that had been induced
It had been suggested that morphine produces tolerance because it does not induce rapid MOPr desensitization and that morphine tolerance occurs following subsequent, as yet unknown, adaptive changes caused by prolonged MOPr signalling (Finn & Whistler, 2001)
Summary
The analgesic, respiratory depressant and rewarding effects of morphine occur through activation of l-opioid receptors (MOPrs; Matthes et al, 1996; Romberg et al, 2003). Tolerance to these in vivo responses develops on prolonged exposure (Roerig et al, 1987; Shippenberg et al, 1989; Smith et al, 1999). Initial studies suggested that morphine does not induce MOPr desensitization in mature neurons (Alvarez et al, 2002), leading to the suggestion that receptor desensitization was not involved in morphine tolerance (Finn & Whistler, 2001). Morphine-induced MOPr desensitization has been observed in mature neurons
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