No abstract

The treatment of severe pain with opioids has thus far been limited by their unwanted central side effects. Recent research promises new approaches, including opioid analgesics acting outside the central nervous system, targeting of opioid peptide-containing immune cells to peripheral damaged tissue, and gene transfer to enhance opioid production at sites of injury.

These trials provide some evidence that in the postoperative pain setting, PCA with opioids, compared with conventional opioid treatment, improve analgesia and decrease the risk of pulmonary complications, and that patients prefer them.

Localized inflammation of a rat's hindpaw elicits an accumulation of ␤ -endorphin-(END) containing immune cells. We investigated the production, release, and antinociceptive effects of lymphocyte-derived END in relation to cell trafficking. In normal animals, END and proopiomelanocortin mRNA were less abundant in circulating lymphocytes than in those residing in lymph nodes (LN), suggesting that a finite cell population produces END and homes to LN. Inflammation increased proopiomelanocortin mRNA in cells from noninflamed and inflamed LN. However, END content was increased only in inflamed paw tissue and noninflamed LN-immune cells. Accordingly, corticotropin-releasing factor and IL-1 ␤ released significantly more END from noninflamed than from inflamed LN-immune cells. This secretion was receptor specific, calcium dependent, and mimicked by potassium, consistent with vesicular release. Finally, both agents, injected into the inflamed paw, induced analgesia which was blocked by the co-administration of antiserum against END. Together, these findings suggest that END-producing lymphocytes home to inflamed tissue where they secrete END to reduce pain. Afterwards they migrate to the regional LN, depleted of the peptide. Consistent with this notion, immunofluorescence studies of cell suspensions revealed that END is contained predominantly within memory-type T cells. Thus, the immune system is important for the control of inflammatory pain. This has implications for the understanding of pain in immunosuppressed conditions like cancer or AIDS. ( J. Clin. Invest.

Opioid receptors have been demonstrated on sensory nerves in both inflamed and normal subcutaneous tissue but locally applied opioid agonists produce analgesia in inflamed tissue only. Inflammation confers a disruption of the perineurial barrier that can also be induced deliberately by hyperosmolar solutions. The present study examines at which stage of Freund's adjuvant-induced inflammation peripheral opioid analgesic effects become manifest and whether a perineurial defect contributes to the appearance of such effects. To this end we have monitored the temporal evolution of inflammatory signs (swelling, temperature, hyperalgesia) and of peripheral antinociceptive effects (by the paw pressure test) of mu-, delta-, and kappa-selective opioids. Using horseradish peroxidase histochemistry, the perineurial barrier was assessed in normal and inflamed tissue and following its artificial disruption by hyperosmolar saline and mannitol in vivo. Finally, we sought to elicit analgesia in normal tissue by the concomitant application of mannitol and receptor-selective opioids or by an extremely lipophilic opioid agonist (fentanyl). We found that peripheral opioid antinociception and perineurial leakage occur simultaneously at a very early stage (within 12 hr) of the inflammatory reaction and that both can be mimicked by the administration of hyperosmolar solutions in normal tissue. Fentanyl produced peripheral antinociception in noninflamed tissue that was potentiated by mannitol or inflammation. Our findings demonstrate that the perineurium is a crucial determinant for peripheral opioid analgesia and that the efficacy of locally applied hydrophilic or lipophilic neuromodulatory compounds can be improved dramatically by the concomitant modulation of perineurial permeability.(ABSTRACT TRUNCATED AT 250 WORDS)