Inhibitory Pathways; Endogenous Opiates

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Inhibitory Pathways Endogenous Opiates

• PHOL G008 Fundamentals of Pain
• Lecture by Bruce Lynn
• Director, MSc School of Human Health and
  Performance, UCL

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Box brain!!
F
C
SC
MO
P
MID
DI
SC Spinal Cord
MO Medulla (oblongata)
P Pons
C Cerebellum
MID Midbrain (Mesencephalon)
DI Diencephalon (Thalamus Hypothalamus)
F Forebrain (Cerebral Cortex Deep nuclei, e.g. amygdala)
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Periaqueductal gray (PAG)
F
C
SC
MO
P
MID
DI
PAG

• Midbrain
• Stimulation leads to spatially widespread but
  modality specific affect.
• Analgesia, not anaesthesia.
• No direct fibres to spinal cord, but stimulation
  leads to inhibition in the cord. So what is the
  relay?

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Nucleus Raphe Magnus (NRM) RostralVentral Medulla
(RVM)
F
C
SC
MO
P
MID
DI
PAG
RVM

• Nucleus raphe magnus (NRM) described first as
  link between PAG and spinal cord
• Distinctive feature - many neurones contain 5HT
  (serotonin)
• Now clear adjacent parts of reticular formation
  also signal from PAG to spinal cord
• So Rostral Ventral Medulla (RVM) considered as
  single functional unit
• Stimulation leads to analgesia and to inhibition
  in the cord.

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• Further details on descending inhibitory pathways
• Important role for DLPT (Dorsolateral
  ponto-mesencephalic tegmentum!!)
• Adjacent to caudal PAG
• Contains major groups of neurones that contain
  nor-adrenaline, including the Locus Coeruleus
• Some direct connections to dorsal horn
• Extensive connections with PAG and RVM
• Note fibres from brainstem to spinal cord
  (reticulospinal) are not all inhibitory some
  are facilitatory.

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• Physiological control of descending inhibition
• Negative feedback.
• Not generally considered important in pain
  pathways not useful to limit pain signals due
  to importance in triggering protective behaviour.
  
• But noxious stimulation can activate descending
  neurones, perhaps via medullary reticular
  formation (nucleus reticularis paragigantocellular
  is, NRPG) to PAG and RVM.
• Basis for one pain distracting from another?

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• Physiological control of descending inhibition,
  cont.
• Stress produced analgesia (SPA).
• Many accounts of people ignoring injuries when
  stressed, e.g. during sports contests, in battle.
  
• Animal studies show at least partly due to
  activation of PAG/RVM system.
• Possible role for amygdala, hypothalamus, some
  cortical regions (insula) that are also involved
  in other aspects of stress responses (hormonal,
  cardiovascular).
• Note that PAG/RVM system is also part of
  cardiovascular control system for stress
  responses.
• Exercise induced analgesia.
• May be distinct from SPA. Controversial.

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Summary of major components of descending
inhibitory system
Hypothalamus
Amygdala
Frontal cortex
PAG
DLPT
RVM
NRPG
Dorsal Horn
Nociceptive Input
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Endogenous opioids Enkephalins Endorphins Dynorph
ins Endomorphins Plus Nociceptin mixed
analgesic and hyperalgesic actions
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• Endogenous opioids.
• Enkephalins.
• Small peptides, 5 amino acids
• 2 versions, leucine enkephalin, methionine
  enkephalin, differ by one amino acid.
• Synthesised in parallel, similar actions.
• Inhibitory neurotransmitters, mostly small
  interneurones, in PAG, RVM, dorsal horn plus
  several other sites.

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• Endogenous opioids.
• Endorphins.
• Mostly beta-endorphin.
• 31 amino acid peptide, includes met-enkephalin
  sequence, but synthesised separately
• Synthesised from precursor that also creates
  melanocyte stimulating hormone and corticotrophin
  (adrenal cortex-stimulating hormone).
• Found in pituitary and hypothalamus.
• Beta endorphin containing nerve fibres spread
  widely from neurones in the hypothalamus, to make
  inhibitory contacts with target neurones in
  regions including the PAG, but not significantly
  the RVM

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• Endogenous opioids.
• Dynorphins.
• Several forms, 10-17 amino acids.
• Include Leu-enkephalin sequence in structure, but
  synthesised independently.
• Endomorphins.
• 2 forms, both just 4 amino acids.
• No homology to other opioids.
• Recently discovered, importance yet to be
  established.

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Opiate Receptors ? Mu (MOR) ? Delta (DOR) ?
Kappa (KOR) All G-protein/cAMP linked Can also
be coupled to ion channels independent of
G-proteins. Mu most important for analgesic
actions. Delta predominantly analgesia. Kappa
more complex, can be analgesic or hyperalgesic.
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Extent of Laminae I and II in the spinal cord
shown by staining a peptide found in small fibre
primary afferents
Photomicrographs illustrating calcitonin
gene-related peptide (CGRP) immunolabeling (i.e.
using a specific antibody) in the dorsal horn of
the C7 segment after C4T2 rhizotomy. C
Ipsilateral to the rhizotomy, D contralateral.
Note the absence of staining in the medial part
of C7 segment when seven consecutive roots are
cut. Calibration bar equals 200 ?m.
From Catherine Abbadie et al., Brain Research 930
(2002) 150162
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Distribution of endogenous opiate receptor
compared with CGRP in rat cord
Staining for CGRP as in previous slide.
Calibration bar equals 200 ?m.
Staining for the delta opiate receptor
Photomicrographs of the C7 segment after C4T2
rhizotomy. C Ipsilateral to the rhizotomy, D
contralateral. Note (1) the staining is very
similar for both markers, i.e. delta opiate
receptors are mostly in laminae I and II and (2)
marked reduction of staining on the rhizotomy
side for the delta receptor indicating that a lot
of the receptors are on the terminals of primary
afferents.
From Catherine Abbadie et al., Brain Research 930
(2002) 150162
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Endogenous opiates can cause post or pre synaptic
inhibition
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Endogenous control of opiate actions
Endogenous anti-opiate CCK8. CCK8, a short
version of cholecystokinin, is released from
neurones in RVM and PAG and acts as a functional
antagonist to opioid actions. CCK8 antagonists
can enhance opioid actions. Nociceptin may also
act as a functional antagonist in the brain
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• Exogenous opiates
• Examples morphine, codeine
• Act by mimicking endogenous opiates and
  activating inhibitory systems, notably the long
  descending ones.
• Spinal analgesia also achievable by mimicking
  spinal enkephalins.
• Major actions of exogenous opiates like morphine
  are via mu receptor.
• Opiates are excellent analgesics for most acute
  pains and for some chronic pains (cancer, but
  less for neuropathic or inflammatory).
• Problems due to side-effects, tolerance and
  addiction.
• Side-effects, euphoria/dysphoria, constipation,
  respiratory depression, nausea/vomiting.
• Tolerance and addiction may not be too much of a
  problem in pain control.
• Antagonists. Naloxone, naltrexone. Excellent,
  selective antagonists for exogenous and
  endogenous opioids.

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Role of endogenous opioids in placebo response,
SPA etc Existence of antagonists with minimal
side-effects allows double-blind assessment of
opioid involvement in a number of analgesic
states. There is evidence for an opioid
component in the placebo response, in
stress-produced analgesia (SPA) and in
exercise-induced analgesia. SPA is also
accompanied by beta-endorphin release
systemically from the pituitary but what is
target, if any? Note that it is unusual for
naloxone to block the entire effect of SPA, so
there may be important non-opioid components too.
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• Endogenous opioids.
• Summary
• 4 families of endogenous opioids enkephalins,
  endorphins, dynorphins, endomorphins.
• 3 membrane receptors mu, delta and kappa.
• Endog. opioids are involved in descending
  inhibitory pathways.
• Exogenous opiates like morphine mimic these pain
  inhibiting actions.
• Selective antagonists have allowed the
  demonstration of opioid components in placebo and
  stress produced analgesia.

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Inhibitory Pathways Endogenous Opiates Reference
List General reviews Fields, H. L., Basbaum, A.
I. Heinricher, M.M. (2005). Central nervous
system mechanisms of pain modulation. In Textbook
of Pain, 5th edn. eds. McMahon, S and
Koltzenburg, M., Chapt 7. Elsevier. Rang, H. P.,
Dale, M. M., Ritter, A. M. (2003). Pharmacology
5th edn. Chapter on Analgesic drugs. Churchill
Livingstone, Edinburgh. Specific
articles Kieffer, B. L. (1999). Opioids first
lessons from knockout mice. Trends in
Pharmacological Sciences 20, 19-26. ter Riet, G.,
de Craen, A. J., de Boer, A., Kessels, A. G.
(1998). Is placebo analgesia mediated by
endogenous opioids? A systematic review. Pain 76
, 273-275. Koltyn, K.F. (2000) Analgesia
following exercise a review. Sports Med. 29,
85-98.