Blythe B. Holmes (1), Jodie J. Rady (1), David J. Smith (2) and James
M. Fujimoto (1,*)
(1) Research Service and Department of Pharmacology and Toxicology, Veterans
Affairs Medical Center, Milwaukee, WI 53295, USA
(2) Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences
Center of West Virginia University, Morgantown, WV 26506, USA
(*) To whom correspondence should be addressed.
Abstract: Intracerebral injection of neurotensin into specific
brain loci in rats produces hyperalgesia due to the release of cholecystokinin
(CCK) in the spinal cord. The present purpose was to show in another species
that neurotensin can antagonize the antinociceptive action of morphine through
the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly
(i.c.v.) at doses higher than 100 ng produced antinociception in the tail
flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized
the antinociceptive action of morphine given intrathecally (i.t.), thus
demonstrating the antianalgesic activity of neurotensin. The rightward shift
in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated
by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum
solution diluted 1:1000). I.t. administration of lorglumide, a CCKA-receptor
antagonist (10 - 1000 ng), and PD135,158, a CCKB-receptor antagonist
(250 - 500 ng), also eliminated the antianalgesic action of neurotensin.
Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v.
involved spinal CCK. This mode of action is similar to that for the antianalgesic
action of supraspinal pentobarbital which also involves spinal CCK.
Keywords: Neurotensin (intracerebroventricular), Antianalgesia, Cholecystokinin
spinal role, Morphine (intrathecal), Spinal cholecystokinin antagonist