Xie Y, Vanderah TW, Ossipov MH, Lai J, Porreca F (2003) A single rostral ventromedial medulla (RVM) treatment with cholecystokinin-saporin (CCK-sap) prevents the development of opioid-induced paradoxical pain and spinal morphine antinociceptive tolerance. Neuroscience 2003 Abstracts 177.4. Society for Neuroscience, New Orleans, LA.
Summary: Sustained morphine elicits tactile and thermal hypersensitivity (opioid-induced paradoxical pain) and antinociceptive tolerance which are mediated through the time-dependent activation of descending facilitation from the RVM. With morphine exposure, CCK expression and/or release may be altered to activate pain facilitatory neurons of the RVM, manifesting as diminished spinal morphine antinociception (antinociceptive tolerance). To explore a possible role of RVM CCK in morphine-induced paradoxical pain and tolerance, CCK-SAP conjugate was used to selectively lesioned RVM neurons expressing CCK receptors. Male S-D rats received a single RVM injection of CCK, SAP or CCK-SAP. Behavioral responses to tactile (von Frey) and thermal (radiant heat) stimuli were normal 3,7,14 and 28 days after injection. RVM CCK microinjection produced tactile and thermal hypersensitivity in uninjured rats 28 days after receiving RVM CCK or SAP, but not in those receiving CCK-SAP, suggesting the probable loss of RVM CCK receptor-expressing cells. 28 days after RVM CCK, SAP or CCK-SAP injections, rats were implanted with placebo or morphine pellets. Morphine pelleted rats pretreated with RVM CCK or SAP developed tactile and thermal hypersensitivity and spinal antinociceptive tolerance. In contrast, animals pretreated with RVM CCK-SAP did not show morphine induced tactile or thermal hypersensitivity and antinociceptive tolerance was not present. Moreover, CCK-SAP, but not CCK or SAP, pretreatment significantly attenuated the antinociceptive effect of RVM morphine. This suggests that RVM CCK activates tonic descending facilitation driving morphine-induced abnormal pain and spinal antinociceptive tolerance. Moreover, these results suggest the possibility that CCK and opioid receptors may colocalize on some RVM neurons which may act to facilitate pain transmission.
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