Catherine P. Cramer

Tonic nociception in neonatal rats

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 injury were similar to those observed in adult rats, both behaviorally and in terms of their responsivity to morphine-induced antinociception. These results provide the first clear-cut evidence of integrated tonic pain responses in the neonate.

Neonatal pain: A comprehensive survey of attitudes and practices

We surveyed 352 physicians board certified in neonatal-perinatal medicine on their attitudes and practices in the area of pain and pain management in neonates and infants. In contrast to earlier surveys of this type, almost all respondents indicated that even the youngest and most premature infants are able to perceive pain, and most reported that they always advocated anesthesia during the intraoperative period. The use of analgesic agents in the postoperative period, however, was more variable. Respondents who indicated that neonates perceived less pain than adults reported seeing fewer signs of pain and using less analgesia in the postoperative period. They were also more likely to believe that analgesics are too dangerous to use in neonates and that physiologic factors such as incomplete myelination of the pain pathways and neural/physical immaturity (factors now known not to play a role) contribute to diminished pain sensitivity. Conversely, respondents who indicated that neonates do not perceive less pain than adults, the majority of respondents, reported seeing more signs of pain and using more medication in the postoperative period. These physicians also believed that the physiologic stress associated with pain can be more dangerous than the analgesics. We conclude that attitudes and reported practices have changed in the area of neonatal pain and pain management. Furthermore, our data indicate that these attitudes significantly predict reported postoperative medicating practices.

The ontogeny of opiate tolerance and withdrawal in infant rats

The acquisition of morphine analgesic tolerance was investigated in neonatal rats. Morphine was found to produce a potent analgesia, as measured by latency to retract a hindpaw from a 52 degree C hotplate, in rat pups as young as 1 day of age. Morphine analgesic tolerance, however, did not develop in rats until the third week of life. Rats given the same daily morphine regimen starting at 15 days of age or older showed rapid tolerance development. The data from four experiments indicate that experience with morphine prior to this age (Day 15) does not impact on the analgesic efficacy of the drug. Similarly, when morphine treatment was discontinued and the rats given a naloxone challenge, withdrawal symptoms were not observed in very young rats. Opiate withdrawal was first detected in rats that started their daily morphine treatment at 30 days of age and were then challenged with naloxone at 52 days of age. Therefore, two correlates of opiate addiction, tolerance and withdrawal, appear to be relatively late-developing phenomena in the rat.

Ecology and Experience

Two worlds merge in the perspective we take for this chapter. One world is derived from behavioral ecology, the other from the discipline of developmental psychobiology. Their amalgamation provides a particularly rich view of behavioral development, one that we believe can stimulate the formulation and testing of new concepts and hypotheses.

Experience during suckling increases weight and volume of rat hippocampus

Changes in brain anatomy resulting from early suckling experience were explored by measuring wet weight of whole brain, cortex, hippocampus and cerebellum in juvenile rats. Rats provided with ample opportunity to nipple-shift, a behavior associated with enhanced maze learning, had much larger hippocampal mass than rats whose nipple-shifting experience had been restricted. No differences were observed in the other areas measured. This effect of experience was confirmed by histological measurement of hippocampus volume following differential rearing.

Suckling in rats extended by continuous living with dams and their preweanling litters

Abstract To evaluate the role of the dam and littermates in weaning, rats were separated from their biological mothers, beginning at 21 days of age, and housed with a succession of dams and their 16–21-day-old litters. Suckling persistence was evaluated every 5 days until rats reached 70 days of age or no longer suckled. Rats housed in such a preweaning environment continued to suckle well past the normal age of weaning. Specifically, 50% suckled until day 55, and 15% suckled until they were 70 days of age and sexually active. In addition, the interactions among three dams and their litters composed of 16–21-day-old pups and a 45–50-day-old rat that had been housed with similar litters were analysed from time-lapse video-recordings. Experimental rats routinely suckled in the nest and withdrew milk from the dam, but did so only when most of the younger pups had already attached. These data suggest that the maternal and social milieu plays a role in the maintenance of suckling behaviour.

The development of morphine-induced antinociception in neonatal rats: A comparison of forepaw, hindpaw, and tail retraction from a thermal stimulus

Two parallel experiments in rats 2-21 days of age investigated the onset and characteristics of morphine-induced antinociception. One measure of reactivity to pain, limb retraction from a hotplate, was utilized for three different limbs (forepaw, hindpaw, and tail) to chart the development of opioid sensitivity. Morphine-induced antinociception, even in 2-day-old rats, was obtained for all limbs, in a dose-related fashion, and reached peak sensitivity at 6-7 days of age. Naltrexone did not affect limb retraction latencies in nonmorphine treated rats at any age. These studies demonstrate early antinociception to low doses of an opiate and establish that the pain system, like positive reinforcement systems, is opiate sensitive.

Ethylketocyclazocine and bremazocine analgesia in neonatal rats

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.

Nutritive and nonnutritive determinants of milk intake of suckling rats.

In order to determine the factors that enhance milk intake during deprivation, albino rats 15, 20, and 25 days of age were subjected, for 8 hr, to one of the following regimens: (1) privation, that is, separation from the dam and food; (2) privation with a maternal, thelectomized female; (3) privation with a maternal female whose nipples had been surgically ligated; (4) separation from the dam and food but receiving three 2% body weight intragastric preloads of milk; (5) with a dam whose nipples had been ligated and receiving the same intragastric preloads as Group 4; and (6) nondeprived rats. Rats were then allowed 45 min to suckle an anesthetized dam that was induced to let down milk every 4 min by intravenous oxytocin infusion. Intake at Day 15 was reduced by the opportunity to suckle, independent of receiving a milk load. This same trend was apparent, although not as strong, among Day 20 rats. By Day 25, nonnutritive suckling during the privation period no longer attenuated milk intake, although preloads did, whether or not they were paired with nonnutritive suckling. Thus, suckling in albino rats becomes increasingly freed from oral demands and more responsive to the nutritive consequences.

Pro-Leu-Gly-NH2 serves as a conditioned stimulus in the acquisition of conditioned tolerance.

The effect of Pro-Leu-Gly-NH2 (MIF) on the acquisition of tolerance to morphine-induced antinociception and its efficacy as a cue predictive of morphine administration was examined. Daily administration of MIF prior to morphine injection did not attenuate the acquisition of tolerance to the antinociceptive properties of morphine, as measured by the latency to hindpaw lick in a hot-plate test of analgesia. When the animals were tested 72 hr later without MIF pretreatment, they appeared to lose tolerance, as indicated by longer latencies to paw lick. These data suggest that in some situations MIF may interfere with the acquisition of tolerance by acting as a cue that reliably predicts the antinociceptive properties of morphine.