Transcript Document

Innovations
in
‘Omnineuromodulation’TM
May 2006
Introduction
• Present a scientific validation for cannabinoids (CBs)
asserting their therapeutic effects through
‘Omnineuromodulation’TM
CBs are CB1 agonists that activate presynaptic CB1
endocannabinoid receptors, which are omnipresent throughout
the Central Nervous System (CNS)
Action on these receptors modulates neuronal signaling in
important brain areas, including those that mediate
nausea/vomiting, appetite, and neuropathic pain
• Review evidence showing how omnineuromodulation
underlies the therapeutic role of CBs in the management
of Chemotherapy-Induced Nausea and Vomiting (CINV),
Cachexia, and Neuropathic Pain (NP)
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The Ubiquitous CB1
• Endocannabinoids are a major
class of neuromodulators, acting
through CB1 receptors primarily
located on CNS neurons
Levels exceed those of nearly all
neurotransmitter receptors1
• Endocannabinoids also activate
CB2 receptors, mainly located on
immune cells in the periphery2
• Exogenous cannabinoids exert their
effects by driving these innate
systems, often mimicking and
enhancing their natural functions
1..Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.
J Support Oncol. 2004 Jul-Aug;2(4):305-14; discussion 314-6. 2. Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 2003; 17: 179-202.
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The Ubiquitous CB1
• The omnipresent central
distribution of CB1 receptors, and
the modulatory effect on neuronal
signaling, has led to the term
‘Omnineuromodulator,’TM
to describe CB action
• Therapeutic effects are primarily
due to CB1 agonist action in CNS
regions that mediate
nausea/vomiting, appetite, and
neuropathic pain
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Omnineuromodulation
• CBs, such as CESAMET™
(nabilone), act on presynaptic
CB1 receptors, similar to innate or
“endo”-cannabinoids
Inhibits the release of excitatory
(e.g., glutamate) and inhibitory
(e.g., GABA) neurotransmitters
• The primary effect on neuronal
signaling appears to be
inhibitory, but network effects
may be complex and, hence,
modulatory in nature
• Endocannabinoids act in reverse
from classical neurotransmitters
by serving as retrograde synaptic
messengers
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A Sequential Overview
of Omnineuromodulation
Neurotransmitter
(NT) released from
vesicles within the
presynaptic neuron
activates the
postsynaptic neuron
Activation of the
postsynaptic
neuron leads to
the biosynthesis
and nonvesicular
release of an
endocannabinoid,
likely via a
calcium mediated
process
The endocannabinoid
diffuses back to and
binds to the
presynaptic CB1
receptor
The CB1 receptor
activates a G protein
which can lead to a
number of presynaptic
downstream events
(e.g., effects on ion
currents) that result in
the inhibition of
neurotransmitter
release
CB agents, acting as
Omnineuromodulators,
circumvent this multistep process by directly
activating CB1
receptors to stimulate
the endogenous CB
system, enhancing its
function
Anti-emetic, Anti-nausea
Effects of Cannabinoids
Causes of nausea and
vomiting/emesis:
Viral illness
Cancer
Chemotherapy
Radiotherapy
• The Nucleus of the
Dorsal Vagal
Complex (DVC)
- NTS
Solitary Tract (NTS)
in the DVC receives
information about:
Blood-borne emetics
via the brainstem
(BS) “Chemoreceptor Trigger
Zone”
Abdominal irritants
via vagal afferents
• NTS neurons, in turn,
project to a BS central
pattern generator,
which coordinates
vomiting behavior
Cortex
Limbic
System
Brainstem
Emetic
Circuitry
Higher cortical and
limbic regions
(governing taste, smell,
sight, pain, memory and
emotion) can suppress
or stimulate
nausea/vomiting
through descending
connections to the BS
emetic circuitry
• Cannabinoids are
thought to exert their
antiemetic effects
primarily via action on
CB1 receptors in the
NTS and higher cortical
and limbic regions
Cortex
Limbic
System
Brainstem
Emetic
Circuitry
Dorsal Vagal
Complex
- NTS
Indirect, partial
actions on 5-HT and
DA signaling via 5HT3 and D2 receptors
are implicated
Potential Action
of Cannabinoids in Cachexia
• Cannabinoids can
stimulate appetite and
increase food intake by:
Acting on CB1
receptors in the
Hypothalamus, which
plays a key role in
homeostatic regulation
of energy balance
Nucleus
Accumbens
Reward Path
Hypothalamus
Feeding
Circuitry
Ventral
Tegmental
Areas (VTA)
[Updated]
Acting on CB1
receptors in the
Nucleus Accumbens
and activating an
important Reward
Path that connects the
VTA and Nucleus
Accumbens, which
enhances
attractiveness/
enjoyment of food,
thus increasing
incentive to eat
• CBs drive the innate
cannabinoid system in
the hypothalamus to
stimulate feeding, and
circumvent the partial
negative control of the
circulating satiety factor
leptin hormone1-2
Hypothalamus
Feeding
Circuitry
Nucleus
Accumbens
Reward Path
Ventral
Tegmental
Area (VTA)
• CBs also increase
motivation to eat through
interaction with the
dopamine and opioid
systems in the Reward
Path1,3
Leptin Hormone
1. Cota et al, 2003
2. Harrold and Williams, 2003
3. Fride et al, 2005
CBs may also promote
feeding by acting on
CB1 receptors in the
Enteric Nervous
System to modulate
gut-derived satiety
signals, such as the
peptide cholecystokinin
(CCK)
CBs may act on CB1
receptors on
Adipocytes to enhance
lipogenesis and induce
weight gain
Adipocytes
Potential Action of Cannabinoids
in Neuropathic Pain (NP)
What is NP?
• NP is caused by primary lesion or dysfunction of the
nervous system
Generally chronic
Highly unresponsive to traditional analgesics
Hallmark symptoms include hyperalgesia and allodynia
• Peripheral and central pathophysiological mechanisms
may be involved, including an overstimulation and
hyperexcitability of nerve paths
• Given the multiple pathologic mechanisms underlying NP
and multiple targeting of CBs, CB agents represent a
promising potential therapy
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• CBs act in the PAG, the
PeriAqueductal
Gray matter
(PAG)
Lateral Tegmental
Noradrenergic (NA)
Cell System
Rostral
Ventromedial
Medulla (RVM)
RVM, and the Lateral
Tegmental NA Cell
System to dampen pain
signals in the spinal
cord
• Specifically, CBs are
thought to decrease
release of the inhibitory
neurotransmitter GABA,
which in turn, activates
(disinhibits) these
natural descending
analgesic pathways
Ventral
Posterolateral
Nucleus (VPL)
CBs weaken ascending
pain messages by
suppressing noxious
stimulus-evoked activity
in the VPL of the
Thalamus, and are
thereby thought to
decrease pain sensitivity
Amygdala
(Emotion)
Amygdala-mediated
analgesic effects of CBs
may diminish the
unpleasant emotional
experience that is a
component of pain
• CBs produce
antinociception in
the SC by modulating
evoked responses of
primary sensory fibers
(nociceptors) in
the Dorsal Horn,
via a presynaptic action
on DRG neurons
Dorsal Root
Ganglion
(DRG)
• CBs act on CB1
Spinal
Cord
(SC)
receptors to inhibit
glutamate release from
nociceptors in the SC,
reducing excitatory
signaling (via NMDA)
that mediates the
central sensitization
of pain
• CBs may act on CB1
Nociceptor
Peripheral
Terminals
receptors located on
the peripheral
terminals of Primary
Sensory Neurons
(Nociceptors) to
inhibit pain
transmission
• CBs may also act on
CB2 receptors on
surrounding immune
cells to decrease
inflammation and
nociceptor excitation,
reducing pain
sensitivity
Cannabinoid and Opioid Synergism
• Combination therapy with CB agents and opioids may be an
effective approach for NP
• CB and opioid systems appear to work synergistically to reduce
pain, by producing analgesic effects in converging brain
pathways via different mechanisms
E.g., both activate the descending analgesic pathway in the
RVM and PAG by blocking inhibitory GABA inputs
• Opioid analgesics are considered less effective for NP than
inflammatory pain, possibly due to depletion of opioid
receptors in the spinal cord following peripheral nerve injury
In contrast, there is an upregulation of CB1 receptors in the
thalamus which may increase analgesic efficacy of CBs in
chronic pain conditions
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Summary
• CB agonists act as Omnineuromodulators
—a term that describes their role in activating CB1
endocannabinoid receptors, which are omnipresent
throughout the CNS and modulate neuronal signaling
• Evidence shows that Omnineuromodulation underlies
the therapeutic role of CB agents in the treatment of
CINV, Cachexia, and NP
• Given potential synergy between CB and opioid systems,
combination therapy for NP may be a more effective
approach
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Approved for the treatment of nausea and vomiting
associated with cancer chemotherapy in patients who
have failed to respond adequately to conventional
antiemetic treatments
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• CESAMET™ delivers:1
Convenient BID dosing: The usual adult dosage is 1 or 2 mg BID
Predictable pharmacokinetics: Peak plasma concentrations occur
within 2 hours following oral administration
Long acting: 8 to 12 hour duration of action
Not detected by the EMIT test2
• In anti-emetic phase III studies, involving 316 cancer patients
receiving a variety of chemotherapeutics (including cisplatin),
CESAMET™ was shown to be superior in efficacy to placebo,
as well as to prochlorperazine, in:1
Reduction of vomiting episodes
Reduction of nausea severity
Improvement in appetite
Investigators’ global impression of efficacy3
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