The long term objective of the proposed research is to enhance our understanding of the perception and control of nociceptive information original from the oro-facial region. The central theme of the investigation is that activation of alpha2-adrenoceptors (alpha2 Ars) and descending noradrenergic pathway from the Kolliker Fuse nucleus (KF=A7 catecholamine cell group) modulate nociceptive information and excitatory amino acid mediated neurotransmission in the medullary dorsal horn (trigeminal nucleus caudalis). Single unit activity of nociceptive neurons including trigeminothalamic neurons will be recorded in the superficial and deeper dorsal horn of the medulla in anesthetized rats. Effects of microinontophoretically applied alpha2-adrenoceptor agonists and antagonists will be tested on the responses evoked by somatosensory stimuli and by activation of excitatory amino acid (EAA) receptors [N-methyl-D-aspartic acid (NMDA), non-NMDA ionotropic and metabotropic receptors]. Effects of activation of alpha2ARRs will be investigated on nociceptive behavior elicited by EAAs. Contribution of noradrenergic neurons in KF to innervation of the medullary dorsal horn will be investigated using neuroanatomical techniques. Effects of stimulation (chemical, electrical) in KF will be investigated on the responses of nociceptive neurons. The contribution of alpha2-adrenoceptors in mediating descending modulation from KF will be determined by microiontophoretic application of alpha2-adrenoceptor antagonists in the medullary dorsal horn. Specific contributions of alpha2AR subtypes in mediating the effects of alpha2 agonists and stimulation in KF will be investigated by using the antisense oligonucleotide technology (antisense knock-down). The proposed studies will enhance our understanding of nociceptive information processing in the medullary dorsal horn and lead to the development of better pain control suggests. The new information will also help in the development of new analgesic which are free of the abuse potential and side effects of narcotics such as morphine.
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