Loss of Antinociceptive Efficacy in Rat Pups Infused with Morphine from Osmotic Minipumps

Stoller, Dawn C.; Thornton, Suzanne R.; Smith, Forrest L.

doi:10.1159/000063250

Cited by 8 publications

(9 citation statements)

References 28 publications

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“…Similarly, mice exposed to chronic noxious stimulation display increased TFLs compared to controls, and a significant two-fold increase in the ED50 of morphine in response to abdominal constriction (42). As noxious stimulation during the neonatal period leads to increased activation of opioid systems in a manner analogous to the repeated application of exogenous opiates, these studies provide evidence that neonatal injury produces cross-tolerance to the analgesic effects of morphine thereby decreasing the subsequent effectiveness of morphine (43, 44). Again interestingly, exposure to morphine neonatally did not result in a significant shift in ED50 values.…”

Section: Discussionmentioning

confidence: 87%

Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats

2008

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Despite mounting evidence on the importance of pain management in preterm infants, clinical use of analgesics in this population is limited. Our previous studies have shown that neonatal inflammation results in long-term alterations in adult somatosensory thresholds, characterized by decreased baseline nociceptive sensitivity, and enhanced hyperalgesia after a subsequent inflammatory insult. The present studies were conducted to determine whether preemptive morphine attenuates these negative consequences. At P0, pups received an injection of morphine sulfate before an intraplantar injection of 1% carrageenan. Control pups received either saline (SAL) followed by intraplantar carrageenan, morphine sulfate followed by intraplantar SAL, or SAL followed by intraplantar SAL. Preemptive morphine significantly attenuated neonatal injuryinduced hypoalgesia in adolescence and adulthood. Similarly, morphine pretreated animals displayed significantly less hyperalgesia and recovered faster from a subsequent inflammatory insult compared with controls. Neonatal morphine had no significant effect on morphine analgesia in adulthood. Interestingly, neonatally injured animals that did not receive morphine displayed a significant rightward shift in the morphine dose-response cuve in the absence of peripheral inflammation. Together, these results demonstrate that preemptive morphine significantly attenuates the long-term behavioral impact of neonatal inflammatory injury. U ntil the late 1980s, many in the medical community believed that neonates were incapable of experiencing pain (1). It is now well established, however, that premature infants are highly responsive to noxious stimulation (2,3) and generate developmentally specific and distinct responses to noxious stimuli (4,5). Nociceptive responses to noxious stimulation have been demonstrated in preterm neonates using an array of physiologic, biochemical, and behavioral measures (6,7). Cortical activation has also been reported in response to noxious stimulation in preterm neonates at 25 wk, suggesting the potential for higher level processing of pain (8,9).Accumulating evidence indicates that exposure to invasive procedures during the neonatal period leads to both short-and long-term alterations in nociceptive processing (10 -13). For example, a higher frequency of invasive procedures in preterm infants has been associated with dampened pain responses at 32 wk of age (14). Decreased facial responsiveness to immunization at 4 and 8 mo (15), and blunted pain sensitivity has also been reported in former preterm neonates (10).Animal studies have also reported that neonatal injury induces long-term alterations in somatic and visceral sensitivity (12,13,16). In particular, animals that received intraplantar carrageenan (CGN) at birth display significant hypoalgesia in the previously injured and uninjured paws in adulthood (12,13). Similar changes in nociceptive sensitivity have also been reported using intraplantar formalin (17). Neonatal injury also results in enhanced hy...

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Section: Discussionmentioning

confidence: 87%

Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats

2008

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“…1). In our previous study of P9 and P17 rats, as the minipump infusion dose was increased for each group of rats, E max values for acutely administered morphine were decreased in a dose-dependent fashion [28]. In the previous study, the nociceptive stimulus temperature for the tail-flick test was held constant, while varying the morphine infusion dose.…”

Section: Behavioral Expression Of Morphine Tolerance In P17 Ratsmentioning

confidence: 96%

“…219 to 842.3]). Finally, μ opioid receptor antagonists like naloxone or naltrexone were not tested since rat pups experience withdrawal signs and loss of antinociception upon injection [28,33].…”

Section: Influence Of Water Bath Temperature On the Efficacy Of Morphinementioning

confidence: 99%

“…Studies have shown that repetitive administration of morphine in postnatal rats results in the development of tolerance [2,28,33,36]. However, continuous administration of morphine by osmotic minipumps results in a decrease in the antinociceptive efficacy of morphine and morphine is unable to elicit a percent of maximum possible effect (%MPE) greater than 50% [28].…”

Section: Introductionmentioning

confidence: 99%

“…However, continuous administration of morphine by osmotic minipumps results in a decrease in the antinociceptive efficacy of morphine and morphine is unable to elicit a percent of maximum possible effect (%MPE) greater than 50% [28]. This finding is interesting in that it is in contrast to morphine tolerance dose response curves in adult rats where morphine is fully efficacious in tolerant animals [7,15].…”

Section: Introductionmentioning

confidence: 99%

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Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

2007

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We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine-than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The deltaopioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [ 35 S]GTPγS and [ 3 H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [ 35 S]GTPγS binding. Furthermore, [ 3 H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups.

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Endogenous opiates and behavior: 2002

Bodnar

Hadjimarkou

2003

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Loss of Antinociceptive Efficacy in Rat Pups Infused with Morphine from Osmotic Minipumps

Cited by 8 publications

References 28 publications

Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats

Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

Endogenous opiates and behavior: 2002

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