Research ReportNeonatal morphine enhances nociception and decreases analgesia in young rats
Introduction
Twenty years ago, pain was not mentioned in the textbooks of pediatric medicine due to several misconceptions, including the mistaken notions that: 1) infants and children did not feel pain, 2) they would not remember the pain, 3) pain built character, and 4) opiates were too dangerous to use. The reality is that infants and children not only experience pain but may in fact have decreased pain thresholds and increased physiological responses to both noxious and innocuous stimuli as compared to older children and adults (Craig et al., 1993, Grunau et al., 1994, Johnston et al., 1996, Johnston et al., 1995). Of even greater consequence is the recognition that early painful experiences may have long-term effects on later pain behaviors (Johnston et al., 1996, Fitzgerald et al., 1989, Grunau et al., 2006, Grunau et al., 1994, Oberlander et al., 2000, Peters et al., 2005, Ruda et al., 2000, Saigal et al., 1994, Taddio and Katz, 2005, Taddio et al., 1997). The abnormal behavioral and physiological responses of early pain-exposed infants to future noxious stimuli vary depending on the timing of the neonatal insult and the use of anesthesia (Taddio and Katz, 2005). Basic science studies using rodent models of neonatal pain to assess long-term alterations in nociception support the clinical evidence of long-term alterations in pain processing following neonatal pain experience (Alvares et al., 2000, Anand et al., 1999, Lidow et al., 2001, Lidow, 2002, Ruda et al., 2000).
With these monumental changes in perspective on pain during infancy and early childhood there has been increased focus on pediatric pain management. With the recognition of the long-term effects of under-treated pain in infants and children there has been an increase in the use of analgesic agents in this patient population. Opioid analgesics remain the “gold standard” for pain relief in acute pain management in the hospital setting. Currently, human infants and children are routinely treated with opioids for pain relief, especially with chronic opioid exposure for sedation to permit mechanical ventilation in the intensive care units. Unfortunately, more than 48% of infants and children administered therapeutic doses of intravenous opioids in the intensive care units demonstrate symptoms of opiate withdrawal (Arnold et al., 1990, Franck and Vilardi, 1995, Franck et al., 1998, French and Nocera, 1994, Norton, 1988).
In the adult population opioids can produce a paradoxical hyperalgesia (Angst and Clark, 2006) that manifests both during withdrawal (Angst et al., 2003) as well as while undergoing chronic therapy (Chu et al., 2006). A prolonged decrease in pain threshold is reported in adult methadone maintenance patients compared to non-addict siblings and interestingly the decrease in pain threshold also remains lower in ex-opioid addicts as compared to a control population that does not have a substance abuse disorder (Compton, 1994, Compton et al., 2000, Compton et al., 2001, Doverty et al., 2001a, Doverty et al., 2001b, Ho and Dole, 1979). Whether exposure to opioids in pre-term infants causes long-term alterations in pain thresholds is currently unknown.
Our laboratory has recently shown that acute morphine administration in young rats produces spontaneous or precipitated withdrawal-associated pain hypersensitivity (Sweitzer et al., 2004a, Sweitzer et al., 2004b, Zissen et al., 2007) that is equivalent to that observed in adults (Bederson et al., 1990, Kim et al., 1990). Furthermore, this exposure can have lasting effects on inflammatory pain experienced later in childhood (Zissen et al., 2006). Dramatic changes in pain processing and opioid systems (Fitzgerald and Jennings, 1999) in neonates coupled with the repeated morphine exposure in pre-term infants in the neonatal intensive care unit, make it necessary to investigate the possible long-term influence of chronic morphine exposure in neonates on nociceptive pathways and analgesia.
The maturation of nociceptive circuitry is a dynamic and activity-dependent process that begins during prenatal development and extends into postnatal development in both rats and humans (Fitzgerald and Jennings, 1999). A newborn rat is less mature at birth compared to a human and thus, the first postnatal week in a rat is approximately equivalent to the third trimester in a human fetus or a pre-term infant in the neonatal intensive care unit. Furthermore the second to third postnatal week in a rat is approximately equivalent to the first few years of life in a human infant/child. The present study investigated whether administration of morphine in rats during a time period equivalent to exposure of a pre-term human infant in the neonatal intensive care unit (postnatal days 1–9 in a rat) (Andrews and Fitzgerald, 1994, Dobbing, 1981, Fitzgerald et al., 1988) alters mechanical and thermal nociception, exogenous morphine analgesia, and endogenous stress-induced analgesia during childhood and adolescence.
Section snippets
Body weight
Once a day administration of 3 mg/kg morphine subcutaneous on the back above the tail did not change pre-weaning weight gain compared to saline-exposed, handled-control, and naive rats (Table 1). Post-weaning male rats weighed more than female rats but did not differ between treatment groups (data not shown).
Long-term alterations in mechanical and thermal nociception
Morphine exposure from P1 to P9 produced prolonged mechanical allodynia, defined as a decreased mechanical threshold to induce flexion-withdrawal of the paw as compared to saline-exposed,
Discussion
The present study shows that third trimester-equivalent morphine exposure in neonatal rats (1) altered basal nociception as manifested by mechanical allodynia and thermal hyperalgesia until P39 (developmentally equivalent to human adolescent), (2) decreased morphine analgesia on P20 (developmentally equivalent to human pre-pubescent adolescent) and P49 (developmentally equivalent to human young adult), and (3) decreased swim stress-induced analgesia on P29, but not on P49. These data provide
Animals
All the rats used in this study were born from time-pregnant Sprague–Dawley dams (Charles River Laboratories, Raleigh, North Carolina). Rats of both sexes were housed in litters culled at 10–12 rats/dam. The rats were weaned on day 21 (day after morphine dose-response curve) and housed in same sex groups of 3–4 animals. The animals were housed in a 12/12-h light/dark cycle (lights on at 7 a.m.) with food and water available ad libitum. The body weights were measured daily before weaning. All
Acknowledgments
We would like to gratefully acknowledge Dr. Leslie Sargent-Jones for her scientific and editorial support.
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