The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform
Norah N Naughton - One of the best experts on this subject based on the ideXlab platform.
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effects of butorphanol on morphine induced itch and analgesia in primates
Anesthesiology, 2007Co-Authors: Heeseung Lee, Norah N Naughton, James H WoodsAbstract:Spinal administration of Opioids is one of the most frequent analgesic methods in humans.1,2 However, the most common side effect of Spinal morphine administration is itch/pruritus, which sometimes is severe. This lessens the value of Spinal Opioids for pain relief and is treated by different drugs with variable success.3,4 Recent studies have demonstrated that the same μ-opioid receptors (MOR) mediate both intrathecal morphine–induced analgesia and itch/scratching responses in primates, making it difficult to separate these effects.5,6 Therefore, MOR antagonists such as naloxone, although they are effective antipruritics, are not useful because they reverse the opioid analgesia in patients.7-9 Following a different tactic, it has been suggested that activation of κ-opioid receptors (KOR) can attenuate intrathecal morphine–induced itch/scratching responses without disrupting intrathecal morphine analgesia in primates.10 KOR agonists can also inhibit itch/scratching elicited by various pruritogenic agents in rodents.11,12 More importantly, a recent clinical trial showed that a novel KOR agonist, nalfurafine, is effective in treating patients suffering from uremic pruritus.13 These findings support the therapeutic potential of KOR agonists as antipruritics. Butorphanol is an opioid analgesic with partial agonist actions at both MOR and KOR; it displays high affinity for both MOR and KOR and shows low to medium efficacy in activating receptors in cell lines expressing MOR or KOR.14,15 Several clinical studies have shown that butorphanol is effective in alleviating opioid-induced itch.16-18 It is important to study further the relative roles of MOR and KOR in producing butorphanol's analgesic and antipruritic effect in primates. Therefore, using the pharmacologic approach, the aim of this study was to investigate the receptor mechanisms underlying the behavioral effects of butorphanol in monkeys. First, dose–response curves for systemic butorphanol-induced itch and analgesia were determined in the presence and absence of selective MOR and KOR antagonists. Second, the effectiveness of butorphanol as an antipruritic was evaluated in both subcutaneous and intrathecal morphine–induced itch and analgesia. Third, KOR-selective antagonists were used to compare the degrees of KOR and MOR actions underlying the anti-scratching effect of butorphanol.
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an experimental itch model in monkeys characterization of intrathecal morphine induced scratching and antinociception
Anesthesiology, 2000Co-Authors: Norah N NaughtonAbstract:SINCE the first study1 to report that intrathecal morphine produced prolonged pain relief in patients, the intrathecal technique has been widely used for obstetric analgesia and postoperative pain.2-4 It is clear that the application of Spinal Opioids has become one of the most significant breakthroughs in pain management during the last two decades. However, the most common side effect of Spinal opioid administration is pruritus, which sometimes is severe and may lessen the value of Spinal Opioids for pain relief.4,5 A variety of therapeutic agents have been proposed as antipruritics, but they are effective with variable success.4,5 The development of experimental itch models is valuable for identifying potential antipruritic agents and investigating underlying mechanisms. In rodents, intracisternal administration of morphine has been shown to evoke scratching responses.6,7 However, this centrally administered morphine-induced scratching only lasted for 1 h.6 Currently, there is no report indicating that intrathecal morphine induces scratching behaviors in rodents. Although high doses of intrathecal morphine produced allodynia-like behaviors in rats, these effects were not reversed by opioid antagonists.8 In nonhuman primates, intrathecal morphine has been shown to produce prolonged antinociception.9,10 Nevertheless, characterization of intrathecal morphine-induced scratching responses in terms of dose-response and duration has not been systematically evaluated. Therefore, the aim of this study was to establish the pharmacologic basis of intrathecal morphine effects in nonhuman primates for scratching responses and antinociception. The time course and dose dependency of both behavioral end points were evaluated in the same subjects over an extensive dose range. Furthermore, a long-acting opioid antagonist, nalmefene,11,12 was used to assess its capacity in attenuating scratching responses and to determine if opioid receptors were involved differently in scratching and antinociception.
Anthony H Dickenson - One of the best experts on this subject based on the ideXlab platform.
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the effectiveness of Spinal and systemic morphine on rat dorsal horn neuronal responses in the Spinal nerve ligation model of neuropathic pain
Pain, 1999Co-Authors: Rie Suzuki, Victoria Chapman, Anthony H DickensonAbstract:Abstract The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of Spinal versus systemic administration of morphine on the natural and electrically evoked responses of Spinal neurones of rats with a selective Spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In Spinal nerve ligated rats, morphine (0.1–5 μg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1–6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of Spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of Spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the Spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of Spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal Opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.
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electrophysiologic analysis of preemptive effects of Spinal Opioids on n methyl d aspartate receptor mediated events
Anesthesiology, 1994Co-Authors: Victoria Chapman, Jane E Haley, Anthony H DickensonAbstract:Background Spinal N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms may contribute to reduced opioid sensitivity in conditions of pain. The effectiveness of Spinal Opioids in inhibiting NMDA-mediated nociceptive events was assessed with two models. In addition, opioid dose-response curves with preemptive administration were compared with early and late postadministrations. Methods Dorsal horn nociceptive neuronal responses were recorded in the intact halothane anesthetized rat to acute repetitive C-fiber electrical stimulation (0.1 and 0.5 Hz) and to the peripheral injection of 5% formalin. At 0.5 Hz but not at 0.1 Hz, there was an enhanced C-fiber evoked response of dorsal horn neurons elicited by repetitive C-fiber stimulation (wind-up), which is mediated by the NMDA receptor. Formalin produced a biphasic response; the late protracted inflammatory phase was NMDA receptor-mediated. Results With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 micrograms morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadministration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting mu opioid, D-Ala-Gly-MePHe-Gly-ol, given late postadministration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe-Gly-ol produced complete inhibitions. Conclusions NMDA receptor-mediated neuronal responses, such as wind-up and the established second phase of the formalin response, are poorly responsive to Opioids. Dose increases and preemptive Opioids effectively inhibit these NMDA receptor-mediated events.
James H Woods - One of the best experts on this subject based on the ideXlab platform.
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effects of butorphanol on morphine induced itch and analgesia in primates
Anesthesiology, 2007Co-Authors: Heeseung Lee, Norah N Naughton, James H WoodsAbstract:Spinal administration of Opioids is one of the most frequent analgesic methods in humans.1,2 However, the most common side effect of Spinal morphine administration is itch/pruritus, which sometimes is severe. This lessens the value of Spinal Opioids for pain relief and is treated by different drugs with variable success.3,4 Recent studies have demonstrated that the same μ-opioid receptors (MOR) mediate both intrathecal morphine–induced analgesia and itch/scratching responses in primates, making it difficult to separate these effects.5,6 Therefore, MOR antagonists such as naloxone, although they are effective antipruritics, are not useful because they reverse the opioid analgesia in patients.7-9 Following a different tactic, it has been suggested that activation of κ-opioid receptors (KOR) can attenuate intrathecal morphine–induced itch/scratching responses without disrupting intrathecal morphine analgesia in primates.10 KOR agonists can also inhibit itch/scratching elicited by various pruritogenic agents in rodents.11,12 More importantly, a recent clinical trial showed that a novel KOR agonist, nalfurafine, is effective in treating patients suffering from uremic pruritus.13 These findings support the therapeutic potential of KOR agonists as antipruritics. Butorphanol is an opioid analgesic with partial agonist actions at both MOR and KOR; it displays high affinity for both MOR and KOR and shows low to medium efficacy in activating receptors in cell lines expressing MOR or KOR.14,15 Several clinical studies have shown that butorphanol is effective in alleviating opioid-induced itch.16-18 It is important to study further the relative roles of MOR and KOR in producing butorphanol's analgesic and antipruritic effect in primates. Therefore, using the pharmacologic approach, the aim of this study was to investigate the receptor mechanisms underlying the behavioral effects of butorphanol in monkeys. First, dose–response curves for systemic butorphanol-induced itch and analgesia were determined in the presence and absence of selective MOR and KOR antagonists. Second, the effectiveness of butorphanol as an antipruritic was evaluated in both subcutaneous and intrathecal morphine–induced itch and analgesia. Third, KOR-selective antagonists were used to compare the degrees of KOR and MOR actions underlying the anti-scratching effect of butorphanol.
Christopher M. Bernards - One of the best experts on this subject based on the ideXlab platform.
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Recent insights into the pharmacokinetics of Spinal Opioids and the relevance to opioid selection.
Current Opinion in Anesthesiology, 2004Co-Authors: Christopher M. BernardsAbstract:PURPOSE OF REVIEW: Spinal opioid administration was introduced into clinical practice nearly 25 years ago in the hope of producing intense Spinal analgesia that was devoid of the dose-limiting side effects associated with systemic opioid administration. While Spinal opioid administration can clearly be an effective analgesic technique, there is a widespread misconception that any opioid administered epidurally or intrathecally will produce analgesia by a selective Spinal mechanism. This is simply not true; multiple Opioids that are commonly administered Spinally produce analgesia by uptake into the systemic circulation with subsequent redistribution to brainstem opioid receptors. In an effort to help clinicians understand why some Opioids are not suitable for selective Spinal analgesia, this review describes recent insights into the fate of intrathecally and epidurally administered Opioids. RECENT FINDINGS: A series of animal studies published over the last 4 or more years have provided the first measurements of opioid concentration in the epidural space, intrathecal space, Spinal cord and peri-Spinal tissues following intrathecal and epidural opioid administration. These studies characterize, for the first time, the factors governing the rate and extent to which different Opioids redistribute from the epidural and intrathecal spaces to reach target opioid receptors in the Spinal cord dorsal horn. The findings indicate that increasing lipid solubility decreases the Spinal cord bioavailability of Spinally administered Opioids. SUMMARY: These animal data help to explain multiple clinical studies that have demonstrated that the analgesic effect of Spinally administered lipid-soluble Opioids is due in part, if not exclusively, to uptake into plasma and distribution to brainstem opioid receptors.
Victoria Chapman - One of the best experts on this subject based on the ideXlab platform.
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the effectiveness of Spinal and systemic morphine on rat dorsal horn neuronal responses in the Spinal nerve ligation model of neuropathic pain
Pain, 1999Co-Authors: Rie Suzuki, Victoria Chapman, Anthony H DickensonAbstract:Abstract The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of Spinal versus systemic administration of morphine on the natural and electrically evoked responses of Spinal neurones of rats with a selective Spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In Spinal nerve ligated rats, morphine (0.1–5 μg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1–6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of Spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of Spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the Spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of Spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal Opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.
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electrophysiologic analysis of preemptive effects of Spinal Opioids on n methyl d aspartate receptor mediated events
Anesthesiology, 1994Co-Authors: Victoria Chapman, Jane E Haley, Anthony H DickensonAbstract:Background Spinal N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms may contribute to reduced opioid sensitivity in conditions of pain. The effectiveness of Spinal Opioids in inhibiting NMDA-mediated nociceptive events was assessed with two models. In addition, opioid dose-response curves with preemptive administration were compared with early and late postadministrations. Methods Dorsal horn nociceptive neuronal responses were recorded in the intact halothane anesthetized rat to acute repetitive C-fiber electrical stimulation (0.1 and 0.5 Hz) and to the peripheral injection of 5% formalin. At 0.5 Hz but not at 0.1 Hz, there was an enhanced C-fiber evoked response of dorsal horn neurons elicited by repetitive C-fiber stimulation (wind-up), which is mediated by the NMDA receptor. Formalin produced a biphasic response; the late protracted inflammatory phase was NMDA receptor-mediated. Results With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 micrograms morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadministration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting mu opioid, D-Ala-Gly-MePHe-Gly-ol, given late postadministration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe-Gly-ol produced complete inhibitions. Conclusions NMDA receptor-mediated neuronal responses, such as wind-up and the established second phase of the formalin response, are poorly responsive to Opioids. Dose increases and preemptive Opioids effectively inhibit these NMDA receptor-mediated events.