Dopamine (DA) neurons comprising the A11 diencephalospinal system represent the sole source of DA innervation to the spinal cord. These DA neurons project axons throughout the rostro-caudal extent of the spinal cord, terminating predominantly in the dorsal horn. Spinal cord administration of DA and DA agonists results in many diverse neuromodulatory effects on processes such as nociception, locomotion, movement, sexual functions, and regulation of the autonomic nervous system. Many spinal cord DA-mediated functions contain a sex specific component, such as lower nociceptive thresholds and reduced response to analgesia in females. The purpose of the studies described in this dissertation is to examine the anatomy, regulation, and anti-nociceptive functions of A11 diencephalospinal DA neurons in male and female mice. Adult male mice have significantly higher DA concentrations in the lumbar spinal cord than females or males carrying the testicular feminization mutation (tfm) of the androgen receptor gene. Spinal cord DA concentrations are not changed following orchidectomy in adult male mice or testosterone administration to ovariectomized adult female mice. Administration of exogenous testosterone to postnatal day 2 female mice results in DA concentrations in the adult lumbar spinal cord comparable to those of males. Male mice display significantly more lumbar-projecting A11 DA neurons than females, as determined by retrograde tract tracing and immunohistochemistry directed toward tyrosine hydroxylase. There is no sex difference in the activity (DOPAC/DA ratio) of A11 DA neurons under basal conditions, but this activity is higher in the thoracic segment versus lumbar regions of the spinal cord. Blockade of D2 receptors with raclopride has no effect on A11 DA neuronal activity in the spinal cord, revealing a lack of D2 receptor regulatory mechanisms. Blockade of neuronal impulse flow with γ-butyrolactone increases DA concentrations in the spinal cord, indicating a relative high threshold for end-product inhibition of tyrosine hydroxylase in A11 DA neurons. Systemic administration of the μ-opioid agonist morphine led to a dose- and time-dependent increase in spinal cord DA neuronal activity in both male and female mice, which is blocked by the opioid antagonist naloxone. Conversely, the κ-opioid antagonist nor-binaltorphimine increases activity in the lumbar (but not thoracic) segment. Systemic administration of DA agonists increases the latency to escape in the nociceptive hot plate and tail immersion behavioral tests, while depletion of spinal cord DA with the catecholamine-specific neurotoxin 6-OHDA decreases these nociceptive latencies. The present findings reveal: (1) sex differences in the number of A11 DA neurons and lumbar spinal cord DA concentrations, organized by the presence of androgens early in life, (2) that spinal cord DA axon terminals lack pre- and post-synaptic DA receptor-mediated regulation of DA synthesis, but are activated by μ-opioids and inhibited by κ-opioids in a segment-specific manner, and (3) the A11 DA neuronal system is a tonic descending inhibitor of nociceptive processing in male and female mice.
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