1. Mu opioid receptors mediate positive reinforcement following direct or indirect activation and are central to understanding addiction. Recent data from native neurons confirms that mu receptor signaling is strongly dependent on the agonist. 2. Kappa opioid receptors (KOR) are widely expressed in the central nervous system where they mediate opioid analgesia and mood effects. Knockout mice studies show that KOR contributes to perception of visceral pain and mediates the effects of the kappa agonist U-50,488H but not morphine analgesia or reward. 3. Kappa receptors are located throughout the central nervous system including the hypothalamus, periaqueductal gray and claustrum as well as the

1. Opioids
By Dr Andre Mwana Ngoie

13. Mu receptor
• Mu opioid receptors mediate positive reinforcement following
direct (morphine) or indirect (alcohol, cannabinoids, nicotine)
activation, and our understanding of mu receptor function is central
to the development of addiction therapies. Recent data obtained in
native neurons confirm that mu receptor signaling and regulation
are strongly agonist-dependent. Current functional mapping reveals
morphine-activated neurons in the extended amygdala and early
genomic approaches have identified novel mu receptor-associated
proteins. A classification of about 30 genes either promoting or
counteracting the addictive properties of morphine is proposed
from the analysis of knockout mice data. The targeting of effectors
or regulatory proteins, beyond the mu receptor itself, might provide
valuable strategies to treat addictive disorders.

14. Kappa receptor
• What does the kappa receptor do?
• mu-, delta- and kappa-opioid receptors are
widely expressed in the central nervous
system where they mediate the strong
analgesic and mood-altering actions of
opioids, and modulate numerous endogenous
functions.

15. cont
• mu-, delta- and kappa-opioid receptors are widely
expressed in the central nervous system where they
mediate the strong analgesic and mood-altering
actions of opioids, and modulate numerous
endogenous functions.
• To investigate the contribution of the kappa-opioid
receptor (KOR) to opioid function in vivo, we have
generated KOR-deficient mice by gene targeting.
• We show that absence of KOR does not modify
expression of the other components of the opioid
system, and behavioral tests indicate that spontaneous
activity is not altered in mutant mice.

16. cont
• The analysis of responses to various nociceptive stimuli
suggests that the KOR gene product is implicated in the
perception of visceral chemical pain.
• We further demonstrate that KOR is critical to mediate
the hypolocomotor, analgesic and aversive actions of
the prototypic kappa-agonist U-50,488H.
• Finally, our results indicate that this receptor does not
contribute to morphine analgesia and reward, but
participates in the expression of morphine abstinence.
Together, our data demonstrate that the KOR-encoded
receptor plays a modulatory role in specific aspects of
opioid function.

17. cont
• Where is the kappa opioid receptor?
• Kappa opioid receptors are located on
dopamine axon terminals (Svingos et al.,
2001), while mu opioid receptors are not
expressed on striatal dopamine axon terminals
(Trovero et al., 1990).

18. cont
• Similar to mu opioid receptors, kappa and
delta opioid receptors reside in the periphery,
the dorsal root ganglion, the spinal cord, and
in supra spinal regions associated with pain
modulation. Both delta and kappa opioid
agonists have been shown to activate pain
inhibitory pathways in the central nervous
system.

19. Kappa agonist
• What is kappa opioid agonist?
• Promising alternatives to MOAs are kappa-
opioid agonists (KOAs); these agents have
indistinguishable analgesic properties and a
reduced side-effect profile. Development of
novel KOAs has been limited due to untoward
side-effects mediated by centrally-located
KORs, including dysphoria, sedation, and
hallucinations.

20. Kappa location
• Where are the kappa opioid receptors in the
brain?
• 1.2 Distribution of kappa opioid receptor
• Generally speaking, the KOR is spread throughout
most of the entire central nervous system, and
mainly found within the brain (hypothalamus,
periaqueductal gray, and claustrum), spinal cord
(substantiagelatinosa), and pain neurons,
including peripheral and sensory neurons.

21. cont
• Where are mu opiate receptors?
• The three mu delta and kappa opioid
receptors are major receptors for analgesia
and are expressed at central and peripheral
sites within the pain control circuits. Opioid
receptors are also largely distributed in other
neural pathways where they regulate reward
and affective states