PAIN II Flashcards
Pathway to brain
Most axons of lamina I and IV projection neurons cross midline and ascend in the anterolateral quadrant of SC
Terminations of pain pathways and their tract
- Reticular Formation (Spinoreticular Tract)
- Midbrain (Spinomesencephalic Tract)
- Thalamus (Spinothalamic Tract)
Spinoreticular Tract projects to
reticular neurons (alerts to pain) in brainstem
Does the Spinoreticular Tract have topographical organization
NO–Lacks topographical organization
reticular neurons have wide receptive field
What aspects of pain are signalled by the Spinoreticular Tract
general aspects of pain perception
e.g. alerts onset of pain–doesn’t say what or where BUT ALERTS to pain
reticulothalamic tract
Projection from reticular formation to thalamus (second to the spinoreticular tract)
Spinomesencephalic tract–projects to
midbrain periaqueductal gray matter (PAG)
Role of the PAG
interaction between ascending pain signals and descending analgesic information from `emotional centres’ such as amygdala
Spinomesencephalic tract–additional projections
to hypothalamus (lateral parabrachial area), nucleus of solitary tract and amygdala
Role of Spinomesencephalic tract
Autonomic, affective and neuroendocrine responses to pain
Spinothalamic tract: 2 divisions
Lateral–NEW; to VPL
Medial–OLD: to intralaminar thalamic neurons
Spinothalamic tract (lateral division) is ___ (new or old)
NEW; Phylogenetically recent = neospinothalamic tract
Lateral Spinothalamic tract projects to
ventroposteriolateral (VPL) nucleus of thalamus–only 10% of these neurons are nociceptive
Role of the lateral spinothalamic tract
somatotopically organized
localization and discriminative aspects of pain
Further projections of the lateral spinothalamic tract
somatic sensory cortex and parietal lobe
Spinothalamic tract (medial division) is ___ (new or old)
OLD; Phylogenetically old = paleospinothalamic tract
Medial Spinothalamic tract projects to
intralaminar thalamic neurons
Medial Spinothalamic tract organization and input
NOT somatotopic organization
input comes from dorsal horn cells have large receptive fields
Further projections of the Medial Spinothalamic tract
project widely to association and prefrontal cortex
Role of the Medial spinothalamic tract
affective and alerting aspects of pain
This tract alerts you to pain
Spinoreticular tract
This tract is repsonsible for the autonomic, affective and neuroendocrine responses to pain
Spinomesencephalic tract
This tract is somatotopically organized and is responsible for localization and discriminative aspects of pain
Lateral division of the spinothalamic tract
This tract has affective and alerting aspects to pain and projects to the prefrontal and association cortices
Medial division of the Spinothalamic tract
Pain Matrix is made up of:
ACC (anterior cingulate)
PFC
Insular cortex
Somatosensory cortex
Role of pain matrix (higher centers)
Imparting salience and valence of noiceptive stimuli
If pain signals tissue damage, why have endogenous analgesic mechanisms?
Central Mechanisms to suppress pain have significant survival value
Stop the pain while you escape a dangerous situation
Endogenous mechanisms of analgesia need to have ____ so they don’t inhibit pain’s survival value
HIGH threshold of activation
Endogenous opioids
Met Enkephalin (delta), Leu Enkephalin, (delta ) Dynorphin, (kappa) Endorphin, (mu) Orphanin FQ (Nociceptin) (ORL1), Endomorphin 1 and 2 (mu)
Met Enkephalin receptor
delta opioid (DOR)
Leu Enkephalin receptor
delta opioid (DOR)
Dynorphin receptor
kappa opioid (KOR)
Endorphin receptor
mu (MOR)
Orphanin FQ/Nociceptin
ORL1
Endomorphin 1 and 2
mu (MOR)
Mechanism of opioid receptors (simple)
All opioid receptors are Gi/Go coupled
How opioid receptors work (complicated mechanism)
Inhibit adenyl cyclase –> decreased cAMP –> activate GIRK –> hyperpolarization –> N-type Ca channels close –> less NT release
Opioid receptors are (inhib or excit)
INHIBITORY (but effect depends on what type of cell they are on)
Decreased Neurotransmission
Descending analgesic pathways (structure overview)
Amygdala –> PAG –> RVM –> spinal opioid interneurons
pathway held in check by tonic GABAergic inhibition in RVM and PAG
When GABA isn’t on RVM and PAG
descending analgesic pathways can release endogenoys opioids to suppress pain transmission in the dorsal horn of the SC
Under normal physiological conditions the descending analgesic pathways are held in check by
tonic GABAergic inhibition on PAG and RVM
How to trigger analgesia in the descending analgesic pathway
electrical stim of PAG releases endogenous opioids –> these Opioids inhibit inhibitory neurons –> release the inhibition of the RVM and PAG (disinihbition) and allowing the release of endogenous opioids to suppress pain transmission = analgesia
Two cell types in RVM (rostral ventrolateral medulla)
‘ON’ cells = turned on by noxious stim –> pain
‘OFF’ cells = turned off by noxious stim –>analgesia
‘ON’ cells are _____ by noxious stimuli and ____ by opioids; effect:
excited by noxious; inhibited by opioids
= turn off descending pathways and allow you to feel pain
‘OFF’ cells are _____ by noxious stimuli and ____ by opioids; effect:
inhibited by noxious; excited by opioids
= turn on descending analgesic pathways
How do opioids act at the spinal dorsal horn
opioids act presynaptically to inhibit Ca2+ channels and reduce glutamate release from C-fibres and A-delta fibers
Pathways of analgesia at the spinal cord via opioid interneurons
Descening pathways end on opioid interneuron –> opioid released onto presynaptic terminal of afferents –> inhibit Ca2+ channels (less Ca conductance) –> decreased NT release –> reduced EPSP
How opioids worrk on post-synaptic neurons
opioids act to incrrase K+ conductance in post-synaptic neuron –> hyperpolarized –> decreased NT release
helps decrease firing
Mu receptors are found in the…
PAG RVM (rostral ventral medulla) Dorsal horn (substantia gelatinosa) VTA LC Pre-Botzinger region Enteric nervious system
Effects of Mu opioid receptors in the PAG, RVM, and dorsal horn
analgesia
Effects of Mu opioid receptors in the VTA
reinforcing effects (dopaminergic) ADDICTION
Effects of Mu opioid receptors in the LC
somatic effects of physical dependence
LC is an autnomic centre
Effects of Mu opioid receptors in the pre-botz region
respiratory depression
this area sets the resp. rhythmn
Effects of Mu opioid receptors in the enteric nervous system
constipation
Effects of opioids
- Morphine, Heroin, Fentanyl etc.
- Analgesia
- Euphoria
- Sedation (Narcotic)
- Respiratory depression
- Constipation
- Tolerance, dependence, ‘addiction’
- Hypotension
- Pin point pupils (parasymp)
Opioid Interactions with the Immune system may explain
- Sweating and itching responses
- Paradoxical hyperalgesia (more pain with inflammatory response)
- Analgesic effect of naloxone
How can naloxone have Analgesic effects
At low doses has analgesic effect likely due to inhibition of opioid effects on the immune system
Drug addiction is:
- Continued use of drugs despite serious negative consequences
- Compulsive drug seeking activity
- Evidence of withdrawal when drug is unavailable (usually opposite of drug effect)
Behaviours can also be addictive because they are
Rewarding
Reinforcing
Rewarding effects can be (2 possibilities)
positive (e.g. euphoria) or relief of negative symptoms (e.g. pain, anxiety, depression)
Mesolimbic reward pathways
VTA –> NAc
VTA –> basal forebrain/amygdala
VTA –> medial PFC
Micking or potentiating DA in the mesolimbic DA pathway is…
rewarding and reinforcing
All potnetially addictive drugs produce _____ in animals
self administration
Importance of natural reinforcement
Dopaminergic reinforcement is important biologically –promotes activities that allow you to survive and reproduce (food, water, sex, warmth)
AND drugs
Long-term drug treatment leads to
tolerance and dependence/withdrawal
Tolerance
need more drugs for same effect
Dependence
physiologicaly only normal when drug is in system
Animals will self stimulate _____ which activates reward pathway from ___. this is enhanced by ____.
Self stim medial forebrain bundle, activates VTA reward pathway
effect enhanced by addictive drugs (amphetamines, opioids, cocaine, nicotine, PCP, benzodiazepines and ethanol)
Addicitve drugs increase ___ in the ___
DA in the NAc (as seen in microdialysis studies)
DA inhibits GABAergic spiny projection neurons in nucleus accumbens but how this relates to reward is unknown.
How cocaine creates reward
inhibits DA reuptake (more DA –> more inhibition of spiny neurons in NAc = reward)
How amphetamines create reward
reverse reuptake transporter to export DA and inhibits DA storage (so DA is pumped out not stored)
Cocaine and amphetamine _____ increase ___ transmission. Rewarding effects can be blocked by…
directly; DA
Rewarding effects blocked by DA antagonists or by the DA synthesis inhibitor a-methylparatyrosine
Opioid mechanism of reward
2 ways:
disinhibition of VTA (inhibit gaba interneurons –> more DA release)
Direct inhibition of spiny projection neurons in the NAc by DA (inhibition -> reward)
Nicotine reward
not generally behaviourally reinfocring
Directly stimulate VTA –> DA release –> DA inhibits NAc
Ketamine
effectively inhibit neurons in NAc
Blocks NMDA receptors and excitatory glut drive to spiny projection neurons (when spiny projection neurons are inhibited = addiction)
‘On’ cell neuron type/NT type
GABAergic interneuron
on cells are GABAergic interneurons excited by pain –> turn off descending pathway –> allow pain perception
‘Off’ cells function
pain/noxious stim –> inhibit OFF cell –> inhibit spinal inhibitory interneuron (disinhibition of pain)–> no analgesia therefore pain is felt
opioids –> excite off cell (RVM neuron) –> stimulate spinal inhib interneuron –> inhibit pain (= analgesia)
descending analgesic pathway end on ______ which release _____ unto _____ terminals of _____
RESULT:
opioid interneurons, release opioids onto presynaptic terminals of afferents entering the SC
resulting in decreased Ca conductance and therefore decreased NT release
Opioid modulation of K+
opioids directly interact with post-synaptic neurons in the SC –> increase K+ conductance –> hyperpol –> decrease NT release
DA ____ (inhibits/excites) ____ (neuron type) in NAc
inhibits GABAergic spiny projection neurons
unsure how this relates to rewards
Increased DA onto the Nac –>
inhibition of NAc spiny projection neurons = reward
How increased DA creates reward
increased DA onto NAc –> da inhibits spiny projection neurons = addiction/reward
