exposure, or if different Dcc alleles cause differences in function rather than expression. The latter possibility might be caused by one of the identified SNP variants predicted to change amino acid sequence. In this respect the A713V variant is of great interest as it appears to be associated with a high versus low likelihood of developing either OIH or opioid analgesic tolerance. Though the alanine to valine substitution involves two similar hydrophobic amino acids, similar changes have been shown to cause profound changes in glycine receptor function [43]. Importantly, baseline nociceptive thresholds and analgesic potency of morphine were unaltered in heterozygous mice suggesting that reduced DCC availability may still be sufficient to support the basic development and maintenance of primary pain-related circuitry, but that the ability of adult animals to adapt to sustained morphine administration is reduced. For example, changes in the formation of synapses within the spinal cord dorsal horn or alterations in the density of descending modulatory fibers from the medulla, another CNS center strongly associated with opioid adaptations [44, 45], may modulate the Dcc genetic effects. Alternatively, DCC is known to be involved in formation of the locus coeruleus [46], a major brain center linked to descending
