Injury or potentially damaging stimulation of small diameter nerve fibers is sufficient to evoke pain sensation, motor and autonomic reflexes, and the recruitment of descending controls that serve to inhibit subsequent responses to painful stimuli. Nearly all small diameter sensory nerves terminate initially in the dorsal horn of the spinal cord, or its brainstem counterpart, trigeminal subnucleus caudalis. Thus, central neurons that receive direct input from small afferent nerve fibers must play a critical role in mediating the various aspects of pain. The central theme of this application is that the function of central trigeminal neurons can be inferred if their encoding properties and efferent projections can be determined. This theme is explored by using the corneal afferent system, since the corneal is supplied only by small diameter fibers and most corneal stimuli cause pain sensation in humans. Corneal nerves terminate in two spatially discrete brainstem regions: at the transition of trigeminal subnucleus interpolaris with subnucleus caudalis and at the transition of trigeminal subnucleus caudalis with the spinal cord. Three hypotheses are tested with single neuron recording methods by applying criteria, that if satisfied, will lead to inferences of function for trigeminal brainstem neurons that respond to corneal stimuli. Hypothesis 1 states that if central neurons contribute to the sensory-discriminative aspects of corneal pain, then these neurons should encode the intensity of corneal input, project to the sensory thalamus and should be inhibited by systemic morphine. Hypothesis 2 takes advantage of the unique longitudinal organization of the trigeminal brainstem complex to assess the importance of intersubnuclear connections. If morphine acts through a critical caudal relay to modify the activity of neurons at more rostral portions of the nucleus, then local injection of morphine at the subnucleus caudalis/spinal cord transition should alter the activity of corneal-responsive neurons at the subnucleus interpolaris/caudalis transition. Hypothesis 3 states that if the opioid receptor subtypes subserve different roles in modulating activity at the subnucleus caudalis/spinal cord transition, then local application of receptor-selective agonists at this caudal region should have differential effects on corneal-responsive neurons. The results derived from these experiments will provide new information on the properties of neurons necessary for the different aspects of corneal pain and will lead to a better understanding of the role of opioid receptor subtypes in orofacial pain processing.
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