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From: Kofi on 16 Mar 2010 22:49
If this is true, low-dose naltrexone may be acting directly on barrier
function and innate immunity viz. cathelicidin - and rolipram may be
affecting opiate signaling.
Brain Res. 2008 Sep 22;1231:16-24. Epub 2008 Jul 12.
Low doses of cyclic AMP-phosphodiesterase inhibitors rapidly evoke
opioid receptor-mediated thermal hyperalgesia in naive mice which is
converted to prominent analgesia by cotreatment with ultra-low-dose
Crain SM, Shen KF.
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva
University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Systemic (s.c.) injection in naive mice of cyclic AMP-phosphodiesterase
(cAMP-PDE) inhibitors, e.g. 3-isobutyl-1-methylxanthine [(IBMX) or
caffeine, 10 mg/kg] or the more specific cAMP-PDE inhibitor, rolipram (1
mug/kg), rapidly evokes thermal hyperalgesia (lasting >5 h). These
effects appear to be mediated by enhanced excitatory opioid receptor
signaling, as occurs during withdrawal in opioid-dependent mice.
Cotreatment of these mice with ultra-low-dose naltrexone (NTX, 0.1
ng/kg-1 pg/kg, s.c.) results in prominent opioid analgesia (lasting >4
h) even when the dose of rolipram is reduced to 1 pg/kg. Cotreatment of
these cAMP-PDE inhibitors in naive mice with an ultra-low-dose (0.1
ng/kg) of the kappa-opioid receptor antagonist, nor-binaltorphimine
(nor-BNI) or the mu-opioid receptor antagonist, beta-funaltrexamine
(beta-FNA) also results in opioid analgesia. These excitatory effects of
cAMP-PDE inhibitors in naive mice may be mediated by enhanced release of
small amounts of endogenous bimodally-acting (excitatory/inhibitory)
opioid agonists by neurons in nociceptive networks. Ultra-low-dose NTX,
nor-BNI or beta-FNA selectively antagonizes high-efficacy excitatory
(hyperalgesic) Gs-coupled opioid receptor-mediated signaling in naive
mice and results in rapid conversion to inhibitory (analgesic)
Gi/Go-coupled opioid receptor-mediated signaling which normally requires
activation by much higher doses of opioid agonists. Cotreatment with a
low subanalgesic dose of kelatorphan, an inhibitor of multiple
endogenous opioid peptide-degrading enzymes, stabilizes endogenous
opioid agonists released by cAMP-PDE inhibitors, resulting in conversion
of the hyperalgesia to analgesia without requiring selective blockade of
excitatory opioid receptor signaling. The present study provides a novel
pharmacologic paradigm that may facilitate development of valuable
non-narcotic clinical analgesics utilizing cotreatment with
ultra-low-dose rolipram plus ultra-low-dose NTX or related agents.