This claims review supports a growing consensus that opioid-related adverse events are multifactorial and potentially preventable with improvements in assessment of sedation level, monitoring of oxygenation and ventilation, and early response and intervention, particularly within the first 24 h postoperatively.

Although anatomical and neurochemical studies suggest that endogenous opioids act as neurotransmitters1-7, their roles in normal and pathophysiological regulation of synaptic transmission are not defined. Here we examine the actions of prodynorphin-derived opioid peptides in the guinea-pig hippocampus and show that physiological stimulation of the dynorphin-containing dentate granule cells can release endogenous dynorphins, which then activate κ 1 , opioid receptors present in the molecular layer of the dentate gyrus. Activation of κ 1 receptors by either pharmacologically applied agonist or endogenously released peptide reduces excitatory transmission in the dentate gyrus, as shown by a reduction in the excitatory postsnaptic currents evoked by stimulation of the perforant path, a principal excitatory afferent. In addition, released dynorphin peptides were found to block the induction of long-term potentiation (LTP) at the granule cellperforant path synapse. The results indicate that endogenous dynorphins function in this hippocampal circuit as retrograde, inhibitory neurotransmitters.Whole cell recordings were made from granule cells in the guinea-pig hippocampal slice ( Fig. 1) and excitatory postsynaptic currents (e.p.s.cs) were evoked by afferent stimulation either in the molecular layer (to activate perforant path fibres from the entorhinal cortex) or in the hilus (to activate commissural/associational afferents). Opioid receptor activation by the κ 1 selective agonist U69,593 (refs 8,9) at 500 nM significantly reduced (by 41 ± 3%; n = 8) the amplitude of the CNQX-sensitive e.p.s.cs evoked by perforant path stimulation without affecting granule cell input conductance (Fig. 1b). This effect was reversed by the κ 1 selective antagonist10, 11, norbinaltorphimine at 100 nM (Fig. 1b). In contrast, the CNQX-sensitive component of the e.p.s.cs evoked by hilar stimulation was not significantly affected by κ 1 receptor activation (n = 4) (Fig. 1b). Thus, κ 1 receptors appear to be selectively expressed on perforant path terminals and to inhibit glutamate release rather than directly affecting the postsynaptic cell or its response to glutamate.To determine whether endogenous opioids also modulate the release of glutamate from perforant path afferents, we stimulated granule cells using a paradigm previously shown to release dynorphins by antidromic activation of granule cell axons in the hilus of the dentaté gyrus6. Perforant path-evoked e.p.s.cs were monitored before and after dynorphin release, and e.p.s.c. amplitudes were found to be significantly reduced (by 21 ± 2%, n = 15) following hilar (Fig. 2).The reduction in e.p.s.c. amplitude caused by hilar stimulation was blocked by 1 μM naloxone (0 ± 5% change; n = 5) at 2 min after hilar high-frequency stimulation (HHFS). In the representative cell shown, hilar stimulation reduced perforant path e.p.s.cs by 26%, whereas in the presence of naloxone, perforant path e.p.s.c. amplitude was reduced only 4% following hilar stimulation (Fig. 2b). This antagonism ...

The cytotoxic activity of natural killer cells was investigated in rats subjected to one of two inescapable footshock stress paradigms, both of which induce analgesia, but only one via activation of opioid mechanisms. Splenic natural killer cell activity was suppressed by the opioid, but not the nonopioid, form of stress. This suppression was blocked by the opioid antagonist naltrexone. Similar suppression of natural killer activity was induced by high doses of morphine. These results suggest that endogenous opioid peptides mediate the suppressive effect of certain forms of stress on natural killer cell cytotoxicity.

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4 -L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAPpositive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.