Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat

Complete or partial spinal section at T-8 has been shown to block tactile a llodynia but not thermal hyperalgesia following L-5/L-6 spinal nerve ligati on (SNL), suggesting the supraspinal integration of allodynia in neuropathi c pain. In the present study, the possibility of mediation of nerve injury- associated pain through tonic activity of descending nociceptive facilitati on arising from the rostroventromedial medulla (RVM) was investigated. Spec ifically. the actions of brainstem cholecystokinin and the possible importa nce of sustained afferent input from injured nerve fibers were determined u sing pharmacological and physiological approaches in rats with SNL. Lidocai ne given bilaterally into the RVM blocked tactile allodynia and thermal hyp eralgesia in SNL rats and was inactive in sham-operated rats. Bilateral inj ection of L365,260 (CCKB receptor antagonist) into the RVM also reversed bo th tactile allodynia and thermal hyperalgesia. Microinjection of CCK-8 (s) into the RVM of naive rats produced a robust tactile allodynic effect and a more modest hyperalgesia. CCK immunoreactivity was not significantly diffe rent between SNL and sham-operated rats. The anti-nociceptive effect of mor phine given into the ventrolateral periaqueductal gray region (PAG) was sub stantially reduced by SNL;. The injection of L365,260 into the RVM or of bu pivacaine at the site of nerve injury restored the potency and efficacy of PAG morphine in SNL rats. These results suggest that changes in supraspinal processing are likely to contribute to the observed poor efficacy of opioi ds in clinical states of neuropathic pain. These data also indicate that th e activation of descending nociceptive facilitatory pathways is important i n the maintenance of neuropathic pain, appears to be dependent on CCK relea se, and may be driven from sustained afferent input from injured nerves to brainstem sites. Collectively, these data support the hypothesis that abnor mal tonic activity of descending facilitation mechanisms may underlie chron ic pain from peripheral nerve injury. (C) 2000 International Association fo r the Study of Pain. Published by Elsevier Science B.V. All rights reserved .