|
[Version formatted for online
viewing]
1
Crain SM; Shen KF
Cholera toxin-B subunit blocks excitatory opioid receptor-mediated hyperalgesic effects in mice, thereby unmasking potent opioid analgesia
and attenuating opioid tolerance/dependence
Brain Res 2001 Nov 16 ;919(1):20-30
ABSTRACT - In a previous study we demonstrated that injection (i.p.) of low
doses of GM1 ganglioside in mice rapidly attenuates morphine's analgesic
effects. This result is consonant with our electrophysiologic studies in
nociceptive types of dorsal root ganglion (DRG) neurons in culture, which
showed that exogenous GM1 rapidly increased the efficacy of excitatory
(Gs-coupled) opioid receptor functions. By contrast, treatment of DRG
neurons with the non-toxic B-subunit of cholera toxin (CTX-B) which binds
selectively to GM1, blocked the excitatory, but not inhibitory, effects of
morphine and other bimodally-acting opioid agonists, thereby resulting in
a net increase in inhibitory opioid potency. The present study provides
more direct evidence that endogenous GM1 plays a physiologic role in
regulating excitatory opioid receptor functions in vivo by demonstrating
that cotreatment with remarkably low doses of CTX-B (10 ng/kg, s.c.)
selectively blocks hyperalgesic effects elicited by morphine or by a kappa
opioid agonist, thereby unmasking potent opioid analgesia. These results
are comparable to the effects of cotreatment of mice with morphine plus an
ultra-low dose of the opioid antagonist, naltrexone (NTX) which blocks
opioid-induced hyperalgesic effects, unmasking potent opioid analgesia.
Low-dose NTX selectively blocks excitatory opioid receptors at their
recognition site, whereas CTX-B binds to, and interferes with, a putative
allosteric GM1 regulatory site on excitatory opioid receptors.
Furthermore, chronic cotreatment of mice with morphine plus CTX-B
attenuates development of opioid tolerance and physical dependence, as
previously shown to occur during cotreatment with low-dose NTX.
2
Crain SM; Shen KF
Acute thermal hyperalgesia elicited by low-dose morphine in normal
mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid
analgesia
Brain Res 2001 Jan 5 ;888(1):75-82
ABSTRACT - Our previous electrophysiologic studies on nociceptive types of
dorsal root ganglion (DRG) neurons in culture demonstrated that extremely
low fM-nM concentrations of morphine and many other bimodally-acting mu,
delta and kappa opioid agonists can elicit direct excitatory opioid
receptor-mediated effects, whereas higher (microM) opioid concentrations
evoked inhibitory effects. Cotreatment with pM naloxone or naltrexone (NTX)
plus fM-nM morphine blocked the excitatory effects and unmasked potent
inhibitory effects of these low opioid concentrations. In the present
study, hot-water-immersion tail-flick antinociception assays at 52 degrees
C on mice showed that extremely low doses of morphine (ca. 0.1 microg/kg)
can, in fact, elicit acute hyperalgesic effects, manifested by rapid onset
of decreases in tail- flick latency for periods >3 h after drug
administration. Cotreatment with ultra-low-dose NTX (ca. 1-100 pg/kg)
blocks this opioid-induced hyperalgesia and unmasks potent opioid
analgesia. The consonance of our in vitro and in vivo evidence indicates
that doses of morphine far below those currently required for clinical
treatment of pain may become effective when opioid hyperalgesic effects
are blocked by coadministration of appropriately low doses of opioid
antagonists. This low-dose-morphine cotreatment procedure should markedly
attenuate morphine tolerance, dependence and other aversive side-effects
3
Crain SM; Shen KF
Enhanced analgesic potency and reduced tolerance of morphine in 129/SvEv
mice: evidence for a deficiency in GM1 ganglioside-regulated excitatory
opioid receptor functions
Brain Res 2000 Feb 21 ;856(1-2):227-235
AB - 10-fold higher doses in SW mice. Furthermore, cotreatment of 129/SvEv
mice with morphine plus a low dose of naltrexone (ca. 0.1 microgram/kg)
that markedly enhances and prolongs morphine's antinociceptive effects in
SW mice did not enhance, and often attenuated6 h. The marked GM1- induced
attenuation of morphine's antinociceptive effects in 129/SvEv mice may be
due to conversion of some of the opioid receptors in these mice from an
inhibitory Gi/Go-coupled to an excitatory Gs-coupled mode. Exogenous GM1
supplementation can, therefore, reverse the anomalous lack of morphine
tolerance displayed by this mouse strain in comparison to SW and other
mice. The present study may provide insights into factors that regulate
the marked variability in nociceptive sensitivity and opioid
tolerance/dependence liability among individual humans
4
Crain SM; Shen KF
Antagonists of excitatory opioid receptor functions enhance
morphine's analgesic potency and attenuate opioid tolerance/dependence
liability
Brain Res 2000 Feb 21 ;856(1-2):227-235
ABSTRACT - Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can
markedly enhance the efficacy and specificity of morphine and related
opioid analgesics. Our correlative studies of the cotreatment of
nociceptive types of dorsal-root ganglion neurons in vitro and mice in
vivo with morphine plus specific opioid receptor antagonists have shown
that antagonism of Gs-coupled excitatory opioid receptor functions by
cotreatment with ultra-low doses of clinically available opioid
antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's
antinociceptive potency and simultaneously attenuates opioid tolerance and
dependence. These preclinical studies in vitro and in vivo provide
cellular mechanisms that can readily account for the unexpected
enhancement of morphine's analgesic potency in recent clinical studies of
post-surgical pain patients cotreated with morphine plus low doses of
naloxone or nalmefene. The striking consistency of these multidisciplinary
studies on nociceptive neurons in culture, behavioral assays on mice and
clinical trials on post-surgical pain patients indicates that clinical
treatment of pain can, indeed, be significantly improved by administering
morphine or other conventional opioid analgesics together with
appropriately low doses of an excitatory opioid receptor antagonist
5
Shen KF; Crain SM
Ultra-low doses of naltrexone or etorphine increase morphine's
antinociceptive potency and attenuate tolerance/dependence in mice
SO - Brain Res 1997 May 23 ;757(2):176-190
ABSTRACT - In previous studies we showed that low (pM) concentrations of
naloxone (NLX), naltrexone (NTX) or etorphine selectively antagonize
excitatory, but not inhibitory, opioid receptor-mediated functions in
nociceptive types of sensory neurons in culture. Cotreatment of these
neurons with pM NTX or etorphine not only results in marked enhancement of
the inhibitory potency of acutely applied nM morphine [or other bimodally-
acting (inhibitory/excitatory) opioid agonists], but also prevents
development of cellular manifestations of tolerance and dependence during
chronic exposure to microM morphine. These in vitro studies were confirmed
in vivo by demonstrating that acute cotreatment of mice with morphine plus
a remarkably low dose of NTX (ca. 10 ng/kg) does, in fact, enhance the
antinociceptive potency of morphine, as measured by hot-water tail-flick
assays. Furthermore, chronic cotreatment of mice with morphine plus low
doses of NTX markedly attenuates development of naloxone-precipitated
withdrawal-jumping in physical dependence assays. The present study
provides systematic dose-response analyses indicating that NTX elicited
optimal enhancement of morphine's antinociceptive potency in mice when
co-administered (i.p.) at about 100 ng/kg together with morphine (3
mg/kg). Doses of NTX as low as 1 ng/kg or as high as 1 microg/kg were
still effective, but to a lesser degree. Oral administration of NTX in the
drinking water of mice was equally effective as i.p. injections in
enhancing the antinociceptive potency of acute morphine injections and
even more effective in attenuating development of tolerance and NLX-precipitated
withdrawal-jumping during chronic cotreatment. Cotreatment with a
subanalgesic dose of etorphine (10 ng/kg) was equally effective as NTX in
enhancing morphine's antinociceptive potency and attenuating
withdrawal-jumping after chronic exposure. These studies provide a
rationale for the clinical use of ultra-low-dose NTX or etorphine so as to
increase the antinociceptive potency while attenuating the
tolerance/dependence liability of morphine or other conventional bimodally-acting
opioid analgesics
6
Crain SM; Shen KF
Modulatory effects of Gs-coupled excitatory opioid receptor functions
on opioid analgesia, tolerance, and dependence
Neurochem Res 1996 Nov ;21(11):1347-1351
ABSTRACT - Electrophysiologic studies of opioid effects on nociceptive types of
dorsal root ganglion (DRG) neurons in organotypic cultures have shown that
morphine and most mu, delta, and kappa opioid agonists can elicit bimodal
excitatory as well as inhibitory modulation of the action potential
duration (APD) of these cells. Excitatory opioid effects have been shown
to be mediated by opioid receptors that are coupled via Gs to cyclic
AMP-dependent ionic conductances that prolong the APD, whereas inhibitory
opioid effects are mediated by opioid receptors coupled via Gi/Go to ionic
conductances that shorten the APD. Selective blockade of excitatory opioid
receptor functions by low (ca. pM) concentrations of naloxone, naltrexone,
etorphine and other specific agents markedly increases the inhibitory
potency of morphine or other bimodally acting agonists and attenuates
development of tolerance/dependence. These in vitro studies have been
confirmed by tail-flick assays showing that acute co-treatment of mice
with morphine plus ultra-low-dose naltrexone or etorphine remarkably
enhances the antinociceptive potency of morphine whereas chronic
co-treatment attenuates development of tolerance and naloxone-precipitated
withdrawal-jumping symptoms
7
Crain SM; Shen KF
Ultra-low concentrations of naloxone selectively antagonize
excitatory effects of morphine on sensory neurons, thereby increasing its
antinociceptive potency and attenuating tolerance/dependence during
chronic cotreatment
Proc Natl Acad Sci U S A 1995 Nov 7 ;92(23):10540-10544
ABSTRACT - Ultra-low picomolar concentrations of the opioid antagonists naloxone
(NLX) and naltrexone (NTX) have remarkably potent antagonist actions on
excitatory opioid receptor functions in mouse dorsal root ganglion (DRG)
neurons, whereas higher nanomolar concentrations antagonize excitatory and
inhibitory opioid functions. Pretreatment of naive nociceptive types of
DRG neurons with picomolar concentrations of either antagonist blocks
excitatory prolongation of the Ca(2+)- dependent component of the action
potential duration (APD) elicited by picomolar-nanomolar morphine and
unmasks inhibitory APD shortening. The present study provides a cellular
mechanism to account for previous reports that low doses of NLX and NTX
paradoxically enhance, instead of attenuate, the analgesic effects of
morphine and other opioid agonists. Furthermore, chronic cotreatment of
DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents
the development of (i) tolerance to the inhibitory APD-shortening effects
of high concentrations of morphine and (ii) supersensitivity to the
excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low
(femtomolar-picomolar) concentrations of morphine and other opioid
agonists. These in vitro studies suggested that ultra-low doses of NLX or
NTX that selectively block the excitatory effects of morphine may not only
enhance the analgesic potency of morphine and other bimodally acting
opioid agonists but also markedly attenuate their dependence liability.
Subsequent correlative studies have now demonstrated that cotreatment of
mice with morphine plus ultra-low-dose NTX does, in fact, enhance the
antinociceptive potency of morphine in tail-flick assays and attenuate
development of withdrawal symptoms in chronic, as well as acute, physical
dependence assays
8
Crain SM; Shen KF
Chronic selective activation of excitatory opioid receptor functions
in sensory neurons results in opioid 'dependence' without tolerance
Brain Res 1992 ;597():74-83
ABSTRACT - We previously showed that mouse sensory dorsal root ganglion (DRG)
neurons chronically exposed to 1 microM D-ala2-D-leu5- enkephalin (DADLE)
or morphine for : 2-3 days in culture become tolerant to the usual opioid
inhibitory receptor-mediated effects, i.e. shortening of the duration of
the calcium-dependent component of the action potential (APD), and
supersensitive to opioid excitatory APD-prolonging effects elicited by low
opioid concentrations. Whereas nanomolar concentrations of dynorphin(1-
13) or morphine are generally required to prolong the APD of naive DRG
neurons (by activating excitatory opioid receptors), femtomolar levels
become effective after chronic opioid treatment. Whereas 1-30 nM naloxone
or diprenorphine prevent both excitatory and inhibitory opioid effects but
do not alter the APD of native DRG neurons, both opioid antagonists
unexpectedly prolong the APD of most of the chronic opioid-treated cells.
In the present study, chronic exposure of DRG neurons to 1 microM DADLE
together with cholera toxin-B subunit (which selectively blocks GM1
ganglioside-regulated opioid excitatory, but not inhibitory, receptor
functions) prevented the development of opioid excitatory supersensitivity
and markedly attenuated tolerance to opioid inhibitory effects.
Conversely, sustained exposure of DRG neurons to 1 nM DADLE, which
selectively activates excitatory opioid receptor functions, resulted in
characteristic opioid excitatory supersensitivity but no tolerance. These
results suggest that 'dependence'-like properties can be induced in
chronic opioid-treated sensory neurons in the absence of tolerance. On the
other hand, development of some components of tolerance in these cells may
require sustained activation of both excitatory, as well as inhibitory,
opioid receptor functions
[END]
|
Alexander DeLuca, M.D.