Analgesic efficacy of ketorolac and morphine in neonatal rats (original) (raw)
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Analgesia induced by local plantar injections of opiates in the formalin test in infant rats
Developmental Psychobiology, 2003
Morphine injected locally to the paw of an adult or an infant rat is analgesic. Opiates specific to m and k opioid receptors, and less consistently to d opioid receptors, given locally to the site of injury in adult animals are also analgesic in a variety of models of inflammatory pain. To determine which opioid receptor(s) are involved in local analgesia in the immature animal, agonists specific for m, k, and d opioid receptors were injected into the intraplantar pad in infant rats and the resultant nociceptive behavior and Fos expression assayed in the formalin test. The k opioid receptor agonist U50,488 reduced nociceptive behavior in both phases of the formalin test and reduced Fos expression in the dorsal horn of the lumbar spinal cord, at 3 and 21 days of age. Morphiceptin (m opioid agonist) was analgesic in the 21-day-old pups, but not the 3-day-old pups, measured behaviorally or by Fos expression. DPDPE (d opioid agonist) was not analgesic at either age. We also tested the effects of opioid receptor antagonists on morphine's local analgesic action. Naltrexone, and to a lesser extent the m opioid antagonist CTOP, antagonized morphine's analgesic effect. Kappa and d opioid receptor blockers were inactive. The results demonstrate the ability of the k opioid system to mediate analgesia in the neonate at the site of injury in acute and chronic pain models, that the m opioid agonists are active later in development, but that morphine is analgesic in part through m opioid receptors. ß 2003 Wiley Periodicals, Inc. Dev Psychobiol 42: 111-122, 2003.
Influence of early neonatal experience on nociceptive responses and analgesic effects in rats
Laboratory Animals, 2009
Early maternal separation has profound effects on nociception in rats. Cross-fostering is a standard husbandry procedure used by some commercial breeders. This study aimed to determine if cross-fostering altered nociception and the analgesic efficacy of buprenorphine and morphine. At seven and nine weeks of age, an elevated plus maze was used to assess anxiety and Hargreaves apparatus was used to measure thermal nociception at two intensities in cross-fostered and naturally-reared rats. At 10 weeks of age these rats were assigned to one of three treatment groups: saline, buprenorphine or morphine. The Hargreaves apparatus was used to evaluate the effect of analgesics on nociception. Differences were observed in nociception between the cross-fostered and naturally-reared rats at both intensities. At the lower intensity no significant differences were seen between the cross-fostered and naturally-reared rats post-administration of an analgesic. At the higher intensity significant diff...
Developmental Brain Research, 1987
Patterns of morphine-and ketocyclazocine-induced analgesia in limb withdrawal and tail-flick tests of thermal and mechanical nociception were examined in the preweanling rat. In the forepaw test, morphine was more effective than ketacyclazocine with both thermal and mechanical stimuli. Both drugs first induced analgesia between 3 and 5 days of age. In the tail-flick test, ketocyclazocine-induced analgesia preceded morphine's effects against both thermal and mechanical stimuli by several days. Ketocyclazocine produced robust analgesia between 7 and 10 days of age, while the effects of morphine did not peak until day 14. In the hindpaw, morphine was more effective than ketocyclazocine against a higher intensity mechanical stimulus, while ketocyclazocine was more effective against a lower intensity mechanical stimulus. Morphine-induced analgesia was reversed by lower doses of naloxone than was ketocyclazocineinduced analgesia, regardless of body part tested, against all noxious stimuli. These findings demonstrate differences in morphine-and ketocyclazocine-induced analgesia that are dependent upon age, body topography, stimulus type and intensity and imply different physiologic roles of/~-and x-opioid receptors in analgesia.
Dual effects of brain sparing opioid in newborn rats: Analgesia and hyperalgesia
Neurobiology of Pain, 2018
Effective pain management in neonates without the unwanted central nervous system (CNS) side effects remains an unmet need. To circumvent these central effects we tested the peripherally acting (brain sparing) opioid agonist loperamide in neonate rats. Our results show that: 1) loperamide (1 mg/kg, s.c.) does not affect the thermal withdrawal latency in the normal hind paw while producing antinociception in all pups with an inflamed hind paw. 2) A dose of loperamide 5 times higher resulted in only 6.9 ng/mL of loperamide in the cerebrospinal fluid (CSF), confirming that loperamide minimally crosses the blood-brain barrier (BBB). 3) Unexpectedly, sustained administration of loperamide for 5 days resulted in a hyperalgesic behavior, as well as increased excitability (sensitization) of dorsal root ganglia (DRGs) and spinal nociceptive neurons. This indicates that opioid induced hyperalgesia (OIH) can be induced through the peripheral nervous system. Unless prevented, OIH could in itself be a limiting factor in the use of brain sparing opioids in the neonate.
Ethylketocyclazocine and bremazocine analgesia in neonatal rats
1988
In three experiments we examined the analgesic potency of kappa opioid receptor agonists in 2-and 16-day-old rats. Ethylketocyclazocine (1-50 mg/kg) produced similar dose-and time-dependent increases in the latency to retract a hind paw from a noxious thermal stimulus in rats of both ages. Bremazocine (0.001-10 mg/kg), a kappa agonist with reported antagonist activity at mu receptors, was also effective in producing analgesia in 2-day-old rats. The dose-effect relationship for bremazocine was nonmonotonic. Bremazocine analgesia (0.1 mg/kg) was reversed by both naltrexone and MR2266, a putative kappa opioid antagonist. These results are discussed in terms of the functional integrity of a kappa analgesic system in the developing rat.
Tonic nociception in neonatal rats
Pharmacology Biochemistry and Behavior, 1990
PHARMACOL BIOCHEM BEHAV 36(4) 859-862, 1990.-The issues of whether infants detect noxious stimuli and whether their nociceptive responses are suppressed by, analgesics has been the focus of considerable controversy. Therefore, to more completely assess the nociceptive responses of neonatal rat pups to tonic pain, we tested 3-day-old rat pups using the formalin test. The responses of the young pups to formalin-produced! injub'y were similar to those observed in adult rats, both behaviorally and in terms of their responsivity to morphine-induced antinoeiception. These results provide the first clear-cut evidence of integrated tonic pain responses in the neonate. Morphine Tonic nociception Neonate Rat Formalin test
Long-Lasting Analgesia With Transdermal Fentanyl: A New Approach in Rat Neonatal Research
Frontiers in Pharmacology, 2022
Background: With advances in neonatal care, management of prolonged pain in newborns is a daily concern. In addition to ethical considerations, pain in early life would have long-term effects and consequences. However, its treatment remains inadequate. It was therefore important to develop an experimental model of longlasting analgesia for neonatal research. Materials and Methods: Experiments were performed in six groups of rats with transdermal fentanyl 0, 3, 12, 50, 100, or 200 μg/kg/h from second postnatal day (P2) until weaning. Assessment of analgesia was carried out at P21, with behavioral scores (ranging from 0 to 3) using a 4% formalin test. Plasma levels of fentanyl were determined by UPLC/TQD at P22. Growth rate was investigated. Results: Fentanyl 100 and 200 μg/kg/h reduced scores of formalin-evoked behavioral pain. They increased time spent in pain score 0 (8 min 55 s and 6 min 34 s versus 23 s in controls) as in low pain scores 1 and 2, and decreased time in the most severe pain score 3 (19 min 56 s and 17 min 39 s versus 44 min 15 s). Fentanylemia increased in a dosedependent manner from 50 μg/kg/h (2.36 ± 0.64 ng/ml) to 200 μg/kg/h (8.66 ± 1.80 ng/ ml). Concerning growth, no difference was observed except weaker growth from P17 to P22 with 200 μg/kg/h. Clinically, we noticed no visible side effect from 3 to 100 μg/kg/h. Concomitantly, 200 μg/kg/h was responsible for ophthalmological side effects with appearance of corneal bilateral clouding in 90% pups. No difference was observed between male and female rats. Conclusion: Altogether, results indicate that transdermal fentanyl 100 μg/kg/h is an efficient therapeutic for long-lasting analgesia in lactating pups. This new model provides a useful tool for protection and welfare, and future opportunity for studying long-term health consequences of sustainable neonatal analgesia.
Paracetamol and morphine for infant and neonatal pain; still a long way to go?
Expert Review of Clinical Pharmacology, 2016
Introduction: Pharmacologic pain management in newborns and infants is often based on limited scientific data. To close the knowledge gap, drug-related research in this population is increasingly supported by the authorities, but remains very challenging. This review summarizes the challenges of analgesic studies in newborns and infants on morphine and paracetamol (acetaminophen). Areas covered: Aspects such as the definition and multimodal character of pain are reflected to newborn infants. Specific problems addressed include defining pharmacodynamic endpoints, performing clinical trials in this population and assessing developmental changes in both pharmacokinetics and pharmacodynamics. Expert commentary: Neonatal and infant pain management research faces two major challenges: lack of clear biomarkers and very heterogeneous pharmacokinetics and pharmacodynamics of analgesics. There is a clear call for integral research addressing the multimodality of pain in this population and further developing population pharmacokinetic models towards physiology-based models.