Intrathecal but Not Intravenous Opioids Release Adenosine from the Spinal Cord

Opioids increase spinal release of adenosine in rats, and analgesia from systemic and intrathecal morphine is reduced in animals by adenosine receptor antagonists. We performed 3 studies to determine whether opioid administration also induces adenosine release in humans. To determine the effect of intrathecal opioid exposure, 15 women received intrathecal fentanyl, 50 μg, or saline, and cerebrospinal fluid was sampled at 2-minute intervals for 6 minutes before surgery. In a second study, 8 healthy volunteers received intrathecal morphine, 50 μg, plus fentanyl, 50 μg, with cerebrospinal fluid sampled 20 and 60 minutes later. To determine the effect of intravenous opioid exposure, 9 healthy volunteers received intravenous remifentanil for 60 minutes, and cerebrospinal fluid was sampled before and at the end of the infusion. Adenosine concentrations were similar in the 3 studies before opioid administration. Intrathecal fentanyl or saline did not affect adenosine concentrations during the 6 minutes in the first study. Adenosine concentrations increased significantly 20 and 60 minutes after intrathecal morphine plus fentanyl was administered. In contrast, adenosine concentrations were unaffected by intravenous remifentanil. These results suggest that intrathecal but not systemic opioid analgesia in humans is associated with spinal release of adenosine. Perspective: Although the role of adenosine release in the spinal cord for opioid receptor activation in subsequent analgesia from opioids is controversial in laboratory studies, these clinical data suggest that local opioid receptor stimulation in the spinal cord of humans does release adenosine. Whether adenosine participates in analgesia from spinal opioids in humans is not known, but spinal adenosine itself is analgesic in humans, consistent with an opioid-adenosine role in analgesia.