Cholecystokinin in the Rostral Ventromedial Medulla in Models of Neuropathic Pain and Morphine Administration

Abstract

States of abnormal pain induced by injuries to peripheral nerves share common features with opioid antinociceptive tolerance including mechanical and thermal hypersensitivity. Sustained administration of morphine in humans and in animals induces a state of abnormal pain (i.e., hyperalgesia) and may be associated with the development opioid antinociceptive tolerance. Persistent neuropathic pain states and opioid induced abnormal pain require descending facilitation arising from the rostral ventromedial medulla (RVM). Cholecystokinin (CCK), a pronociceptive peptide, may be up-regulated following opioid treatment and nerve injury in the brain and spinal cord. Therefore, it is hypothesized that CCK in the RVM may be up-regulated by sustained opioid administration and my consequently drive descending pain facilitatory mechanisms to produce hypersensitivity and antinociceptive tolerance.Acute systemic morphine administration produced a potentiation of CCK release in the RVM as measured using microdialysis techniques. Sustained systemic morphine administration sufficient to produce thermal and tactile hypersensitivity resulted in a significant increase in basal CCK release in the RVM. Spinal nerve ligation (SNL) produces similar behavioral hypersensitivity. CCK levels in the RVM also increased following SNL. These findings suggest that endogenous CCK released in the RVM drives descending facilitatory pathways to produce hypersensitivity following sustained morphine administration and neuropathic pain.Disease states such as neuropathic pain offer special challenges in drug design due to system changes that accompany these diseases. Here, novel peptides with agonist binding affinity and bioactivity at δ and μ opioid receptors and simultaneous antagonist activity at CCK receptors have been developed. Using in vivo behavioral measures, it was shown that intrathecal (i.th.) administration of these compounds suppresses the thermal and tactile hypersensitivity caused by spinal nerve ligation (SNL).These studies support the hypothesis that endogenous CCK drives descending pain facilitatory pathways and that bi-functional compounds that act as opioid agonists and CCK antagonists are effective for the treatment of neuropathic pain.