Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors

Abstract

Intrathecal midazolam causes antinociception by combining with spinal cord benzodiazepine receptors. This effect is reversible with doses of naloxone, suggesting involvement of spinal kappa or delta but not mu opioid receptors. The antinociceptive effects of intrathecally administered drugs in the spinal cord were demonstrated by measurements of the electrical current threshold for avoidance behaviour in rats with chronically implanted lumbar intrathecal catheters. A comparison was made of suppression by two opioid selective antagonists (nor-binaltorphimine (kappa selective) and naltrindole (delta selective)) of spinal antinociception caused by equipotent doses of opioids selective for different receptor subtypes (U-50488H (kappa), DSLET and DSBULET (delta), fentanyl (mu)) and the benzodiazepine midazolam. Nor-binaltorphimine selectively suppressed the effects of U-50488H but not midazolam or fentanyl. However, the delta selective antagonist, naltrindole, caused dose-related suppression of antinociception produced by both delta opioid agonists and midazolam with the same ED50 (0.5 nmol). We conclude that intrathecal midazolam caused spinally mediated antinociception in rats by a mechanism involving delta opioid receptor activation.

Efficacy of intrathecal midazolam versus fentanyl for endoscopic urology surgery

“…20 It has also been suggested that intrathecal midazolam is involved in the release of an endogenous opioid acting at spinal delta receptors. 21 Yegin et al 1 reported that addition of 25 μg fentanyl to 18 mg hyperbaric ropivacaine for spinal anesthesia in patients undergoing transurethral resection of the prostate provided postoperative analgesia of approximately 3.5 h; 4 out of 15 patients in fentanyl group had pruritus. Though, the analgesic efficacy of intrathecal fentanyl has not been compared with intrathecal midazolam in normal patients, a recent study demonstrated that addition of 1 mg intrathecal midazolam to bupivacaine produces much longer duration of anesthesia (140 min) as compared with 25 μg intrathecal fentanyl (107 min) in opium abusers undergoing lower limb orthopedic surgery.…”

A comparative study of intrathecal nonopioid adjuvants to hyperbaric bupivacaine for spinal anaesthesia

“…26,27 It also causes release of endogenous opioid acting at spinal delta receptors as naltrinadole, a delta receptor opioid antagonist suppresses its analgesic effect. 28 Thirdly it inhibits adenosine uptake or enhance adenosine release. 25 The use of IT midazolam in humans is reported in at least 18 peer reviewed reports in about 797 patients since 1986.…”

Midazolam in Spinal Anesthesia — Intrathecal or Intravenous?

“…Midazolam administered via intrathecal or epidural routes can produce analgesia, probably due to its GABA mediated action [4]. Other mechanisms of action including its interaction with opiate receptors have also been proposed [10].…”

“…In 1990s, analgesic efficacy of intrathecal midazolam in humans has been demonstrated [7][8][9]. Naltrindole, a δ-selective opioid antagonistic agent, suppresses the antinociceptive effect of intrathecal midazolam, suggesting that intrathecal midazolam is involved in the release of an endogenous opioid acting at spinal δ receptors [10].…”