when developing animals begin to perceive pain. Reflexive withdrawal from noxious stimulation is observed in rodent embryos starting in late gestation, for example, on embryonic day 17 (E17) in the rat fetus (Narayanan et al., 1971). Human fetuses develop stress hormonal and circulatory changes in response to noxious stimuli by 18–20 weeks of gestation; similarly, fetal lambs and rhesus monkeys demonstrate changes in the pituitary-adrenal axis after application of stressors at the late gestation ages of 125 days and 133 days, respectively (Rose et al., 1978; Smith et al., 2000). Behavioral responses to injection of an irritating substance (formalin) into the paw can be seen in rat fetuses as early as E19, and the response correlates with expression of the c-fos protein (an indication of neuronal activation) in the spinal cord by E20 (Yi and Barr, 1997). By birth, neural substrates for perception of noxious stimulation are present in the periphery and spinal cord of the rat pup, although sensory systems are immature and undergo substantial change during the first few weeks after birth. Many neurotransmitters and receptors in pain pathways appear early in development, but their expression may vary—in either direction—during the neonatal period and may take weeks to achieve adult levels. One could argue that the physiologic response to noxious stimuli suggests a correlation with sensitivity to pain (Mahieu-Caputo et al., 2000; Smith et al., 2000). In theory, cortical recognition of pain in a human fetus should occur in the 26th week of gestation with development of thalamocortical connections (Vanhatalo and van Nieuwenhuizen, 2000).

Rat pups show behavioral arousal and withdrawal responses to noxious thermal and mechanical stimuli as early as the first postnatal day (Barr et al., 1992; Blass et al., 1993; Fanselow and Cramer, 1988; Fujinaga et al., 2000). In addition to behavioral responses to injection of irritating chemicals (Abbott and Guy, 1995; McLaughlin et al., 1990), rat pups as young as 3 days show allodynia and hyperalgesia in response to experimentally induced inflammation (Marsh et al., 1999). The behavioral responses of young pups to noxious stimulation are mostly generalized, whole-body responses, such as wriggling, although more localized withdrawal responses are also seen. As pups mature, their responses become more organized and localized and more typical of adult responses.

Dampening of behavioral responses to noxious stimuli, particularly when such opioid drugs as morphine are administered, is also seen within the first few days after birth (McLaughlin et al., 1990; Fanselow and Cramer, 1988) and the sedating effects of such drugs as pentobarbital can be distinguished from the analgesic effect of morphine as early as postnatal day 1 (P1) in the rat pup (Abbott and Guy, 1995). Mature responses to analgesics are seen around the age of 3 weeks in the rat, coinciding with the maturation of supraspinal descending inhibitory processes. Little information is available regarding neonatal precocious mammal responses to analgesics during postnatal development; however, most neonatal animals develop physiologic responses that are consistent with adult responses by the age of 6–8 weeks. In addition, many physiologic differences between neonatal and adult animals—such as the neonate’s greater perme-



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