title: Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat.
abstract: Complete or partial spinal section at T(8) has been shown to block tactile allodynia but not thermal hyperalgesia following L(5)/L(6) spinal nerve ligation (SNL), suggesting the supraspinal integration of allodynia in neuropathic pain. In the present study, the possibility of mediation of nerve injury-associated pain through tonic activity of descending nociceptive facilitation arising from the rostroventromedial medulla (RVM) was investigated. Specifically, the actions of brainstem cholecystokinin and the possible importance of sustained afferent input from injured nerve fibers were determined using pharmacological and physiological approaches in rats with SNL. Lidocaine given bilaterally into the RVM blocked tactile allodynia and thermal hyperalgesia in SNL rats and was inactive in sham-operated rats. Bilateral injection of L365,260 (CCK(B) receptor antagonist) into the RVM also reversed both 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 different between SNL and sham-operated rats. The anti-nociceptive effect of morphine given into the ventrolateral periaqueductal gray region (PAG) was substantially reduced by SNL. The injection of L365,260 into the RVM or of bupivacaine 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 opioids in clinical states of neuropathic pain. These data also indicate that the activation of descending nociceptive facilitatory pathways is important in the maintenance of neuropathic pain, appears to be dependent on CCK release, and may be driven from sustained afferent input from injured nerves to brainstem sites. Collectively, these data support the hypothesis that abnormal tonic activity of descending facilitation mechanisms may underlie chronic pain from peripheral nerve injury.
authors.affiliation: Department of Pharmacology and Anesthesiology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kovelowski
authors.forename: M H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: T P
authors.initials: TP
authors.lastname: Malan
authors.forename: F
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology / Q000627:therapeutic use; D002766:Cholecystokinin / Q000009:adverse effects / Q000502:physiology*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D008012:Lidocaine / Q000494:pharmacology / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010487:Periaqueductal Gray / Q000187:drug effects / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D000779:Anesthetics, Local; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D002766:Cholecystokinin; D008012:Lidocaine