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.

Cholecystokinin in the Rostral Ventromedial Medulla Mediates Opioid-Induced Hyperalgesia and Antinociceptive Tolerance

“…These studies have confirmed and extended our previous observations showing that pharmacological administration of CCK into the RVM, or into sites somewhat dorsal to the RVM (Kovelowski et al, 2000), induces thermal and mechanical hypersensitivity in naive rats. These effects were time dependent, were mediated via the CCK 2 receptors, and were abolished by lesions of the DLF, suggesting activation of a descending pain facilitation mechanism.…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…Spinal nociception is reported to be enhanced via descending facilitation which can contribute to the development and maintenance of chronic pain (Burgess et al, 2002;Kovelowski et al, 2000;Porreca et al, 2002). During acute nociception, both descending facilitatory and inhibitory pathways are activated and are counterbalanced.…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…One hypothesis suggests that central sensitization at the level of the spinal dorsal horn is maintained independently of primary afferent input (Sandkuhler and Liu, 1998) since input from the periphery is reportedly insufficient to maintain spinal modifications in sensory processing and ultimately neuropathic pain (Burgess et al, 2002;Sun et al, 2005;Xie et al, 2005). Another view suggests that mechanisms at the spinal dorsal horn level require continuous facilitatory input from supraspinal structures Carlson et al, 2007;Gardell et al, 2003;Kauppila et al,1998;Kovelowski et al, 2000;Ossipov et al, 2000;Pertovaara et al, 1997Pertovaara et al, , 2001Porreca et al, 2001;Saade et al, 2006aSaade et al, ,b, 2007Suzuki et al, 2002Suzuki et al, , 2004aVeraPortocarrero et al, 2006). However, in both animal models and humans effects of peripheral neuropathy including peripheral neurodegeneration, altered Na + and K + ion channel expression (Coward et al, 2001a,b;Hong et al, 2004;Hong and Wiley, 2006;Joshi et al, 2006;Matthews et al, 2006;Shembalkar et al, 2001), and abnormal impulse discharge (Nordin et al, 1984;Nystrom and Hagbarth, 1981) in sensory afferents have been shown to persist several weeks/months (Casula et al, 2004;Coward et al, 2000;Fried et al, 1991;Kretschmer et al, 2002;Pan et al, 2001;Pertin et al, 2005;Roytta et al, 1999;Seltzer et al, 1991b).…”