Supraspinal opioid delta receptor mediated antinociception: Supraspinal modulation of neuropathic pain

The central objective of this dissertation focuses on the influence of supraspinal descending nociceptive inhibitory and facilitatory systems in the modulation of both nociceptive input and neuropathic pain states due to peripheral nerve injury. Opioid delta-mediated antinociception within the RVM was observed to modulate supraspinally organized nociceptive behavior to acute stimuli. Spinally organized nociceptive behavior was observed to be δ-mediated as well, but appeared to be stimulus intensity dependent. In addition, activation of δ-opioid receptors within the RVM elicited a dose-dependent antinociceptive effect to tonic forms of nociceptive input. Lesioning of the dorsal lateral funiculus (DLF) was observed to block both the antinociceptive effect of δ-opioid receptor activation in the RVM and attenuation of FLI in the lumbar spinal cord. Finally, concurrent administration of delta-opioid receptor selective agonists into the RVM and intrathecally elicited a synergistic antinociceptive effect to acute forms of nociceptive stimuli. Taken together, these studies presented in this dissertation suggest that activation of δ-opioid receptors within the RVM elicits an antinociceptive effect to both acute and tonic forms of nociceptive input by way of a descending nociceptive inhibitory pathway localized within the DLF. Increased levels, or activity, of supraspinal CCK may consequent to tonic activation of an on-cell descending nociceptive facilitatory system and the behavioral signs of neuropathic pain. For example, CCK levels in the caudal brainstem, when quantified by protein immunoassay, were higher in those animals that had received a ligation to the L5/L6 spinal nerves in comparison to sham operated animals. Administration of the CCK(B) receptor antagonist L365,260 into the RVM was observed to reverse both tactile allodynia and thermal hyperalgesia in L5/L6 ligated animals. In addition, administration of CCK-8 sulfate into the RVM was observed to produce tactile allodynia as well as thermal hyperalgesia, but to a lesser extent, in otherwise normal animals. Finally, a loss of morphine efficacy, when administered into the PAG, was restored by the administration of L365,260 into the RVM of L₅/L₆ ligated animals. Taken together, these studies presented in this dissertation suggest the involvement of a supraspinal descending nociceptive facilitatory influence in the modulation of neuropathic pain due to peripheral nerve injury