Melanocortins and Sexual Functions

&

Mechanism

• Injected into 3rd ventricle of rats >erectile response
• a-MSH injected subcutaneously into men> erection (boners, long hard bbboners)

Mechanism

1. Cross blood/brain barrier
2. function as nuerotransmitter
3. activate erectile centers in brain and spinal cord to penis

...Potenial treatment for ED

Leptin

1. Where is it produced?

2. Function (what and where)? and EVIDENCE

3. Issues with leptin levels

1. Adipose tissue produces Leptin; leptin secretion incaties body fat reserves
2. Leptin signals CNS-regulates feeding behavior to maintain normal m*g
3. reduces food intake and body weight
4. Mice defficient in leptin->obese (hyperphagic) and infertile (like me)

Evidence for controlling food intake

• There are leptin receptors on the POMC neurons at 'arcuate nucleus' that synthesize melanocortins
• AC may have a role in infertility (wtf?)
• Major POint: Leptin stim synthesis of melanocortins and may regulate satiety
• Leptin --> 2 pathways (1. CNS, 2. melanocortins)

MC4R (Melanocortin 4 receptor)-

Evidence

• MC4R agonist plays role in food intake
• mutations in MC4R cause obesity

Melanotropins MSH/ACTH influence neuronal function

• alter neurotransmitter synthesis
• alter eletrophysiological aspects of neurotransmission
• alter excitability of nuerons at spinal cord
• influence behavorial function

So...Melanotropins have a role in maintaining normal NS function

Hadley says that mel. are useful in treating aging of NS

Melanosomes-intracellular structure in melanocyte that fills with melanin (granules)- rapidly translocate in cells

1. translocate to dendric processes (periphery)

or

2.  Translocate back to the central part of cell

This regulates dispersion of color on skin surface (lighter or darker)

*MSH regulates movement of melanosomes -> induces outward movement of melanosomes (darker)

Methylxanthines-stimulate melanosmome dispersion

• block PDE (block breakdown of cAMP?)
• Bu-cAMP stimulates melanosome dispersion
• therefore MSH uses cAMP second messenger

*Catacholamines (epinephrine, norep, etc) have both functions! It depends on the receptor....

B-receptors increase cAMP (not MSH receptors) to increase melanosome dispersion

Catecholamines use alpha-adrenoreceptors block (or inhibit) melanosome dispersion (a-adrenoreceptors lower [cAMP])

adrenergic recpetors control melanophores in many groups

• teleosts
• amphibians
• reptiles

Mechanism of MSH function

and Calcium

-MSH/receptor increases cAMP

-leads to transport of Ca from outside of cell into ER or mitochondria

-Cytoplasmic Ca sequestering is required for melanosome dispersion by MSH

-cytoplasmic Ca2+ required for normal receptor function, even though cAMP is a big deal

 (maybe something to do with cell shape/movement)

*We dont know why

*THis is not the case for catacholamine melan. dispers.

Melanin-Concentrating Hormone

-concentrates melanosomes at center of cell, light skin color

-discovered in 1958 in fish pituitary extracts, intermediate lobe

-injected into fish; perinuclear aggregation of melanosomes

-opposing function of MSH

*Catecholamine blocking is different mechanism

MCH and Energy homeostasis

-evidence

-LH

Evidence:

-MCH injected into hypothalamus stimulates feeding

-MCH increases release of orixigenic transmitter (neuropeptide Y)

-decreases release of anorectic peptide MSH

-MCH inhibits LH release (in rats)

-low energy means eat now, bang later

*Starvation suppresses HPT axis, which reduces thyrid hormone.

-MCH reduces TSH...so maybe MCH has strong role in energy homeostasis

Endorphins

-cattle

-similar to _____

Beta lipotropin 9b-LPH)-extracts from cattle

-these peptides have opiatelike activity (they are termed enkephalins)

endorphins - isolated from brain and pituitary with opiate like activity

similar structure to LPH have opiate like activity

-endogenous anti-pain function

Endogenous opiode peptides: Morphine (other drugs)

-things it affects

-receptors

-perception of pain

-conciousness

-motor control

-autonomic function

function via specigic receptors in CNS

*endogenous receptors have endogenous peptides

Endogenous opiode peptides

-how many identified

-precursor proteins

-20 identified

-all derived from 3 precursor molecules

1. proopiomelanocortin
2. proenkephalin
3. prodynorphin

Describe the:

-(analgesic function) normal pain pathway

1. Nocireceptors (pain/damaging stimuli) stimulated at peripheral NS
2. Nueronal information (afferent direction aka toward CNS) toward spine
3. NT's are released at spinal pathway that carries pain info (sensory pain fibers)
4. *Substance P also is released at NT to spine

*substance P enhances nocireceptor signals to pain pathway

Physiological role of opiod peptides

-how does it work

-discuss pain gate

Enkephalin blocks the release of substance P from nerve terminals of sensory pain fibers

-opiate receptors parallel substance P neurons

Pain gate theory:

-allows pain to be conveyed to sensory pathways via spine to brain

-open then pain, closed then no pain

enkephalins close the pain gate (theory), but how?

-block release of substance P

Acupuncture and endogenous opiods

-discuss evidence (naloxene)

with pain, firing rate of neurons increases

-accupuncture suppresses this increase

-naloxene blocks effect of AccuP.; naloxene is an opiate antagonist

-effects of accupuncture are prolonged, suggests endocrine role (not just neuronal)

*Recent things: electroacupuncture effects blocked by naloxene

-high and low frequency stimulation

this helped a dog to walk again

spinal perfusates were analyzed from endogenous opiodes after accupuncture

high frequ -> dynorphins

low frequ -> enkephalins

antagnist of dyn. and enk. inhibited analgesic effects

Endogenous opiods and pain

-periaqueductal grey matter

-cancer

stimulation of paraaqueductal grey matter:

-increases in ventricular endorphins

-relieved intractable pain

Prelim clinical trials

-b-endorphin injections injections cause pain reduction in terminal cancer

Opiod peptide modulate neuronal activity

-endorphins and opiate narcotics

endorphins and opiate narcotics inhibit spontaneously responsive neurons

-cortex

-brain

-caudate nucleus

-thalamus

*receptor has to be present

Opiod peptide modulate neuronal activity

-opiate receptors

3 classes:

1. Delta receptors
2. Mu receptors
3. Kappa receptors

Differ in CNS locations and affinity for ligands

7 spanning membrane receptors

Function via G proteins

Opiod peptide modulate neuronal activity

-morphine and receptor

Mu receptor has ahighest affinity for morphine...

-BUT peripheral injection of morphine stimulates secretion of enkephalins.....--> delta receptors have highest affinity for enkephalins.

THEREFORE...morphine works indirectly through delta-recpetors and enkephalins

Location, BITCH!

-Mu receptors influence analgesic and emotional behavior

hence, located at basal ganglia and limbic system

-Enkephalins work through Mu and Delta rec.

-Dynorphins use K receptors

Opiod peptides and drug addiction

-cAMP and exposure to opiates

-abrupt removal of opiate

-initial exposure to opiates (in vitro) decreases cAMP

-But, with long term exposure...

-more opiates needed to lower cAMP

-increases adenylate cyclase=higher cAMP

abrupt removal of opiate:

-dramatic increase in cAMP levels

-cell is highly sensitive to ligands that increase cAMP

These are withdrawal symptoms

Heroin tastes good

Recent theory:

-heroin (opiod) addicts suffer from endorphin defficiency

Because:

-heroin and endog. opiates use the same recpetor

-long term exposure to heroin causes neg. feedback inhibition (hypothalamus and pituitary)

-causes addicts to suffer endog. opiate defficiency

Neurohormonal Correlates of addicitve drugs

-mesolymbic system

-cocaine vs nicotine

mesolymbic system recieves signals that stimulate euphoric feelings-can be addictive

-stimulation of MS causes groups of neurons to release dopamine

-dopamine activates postsynaptic neurons -> euphoric feeling

-this causes a desire for more of the substance to feel it again

Cocaine: blocks reuptake of dopamine at synaptic terminals-prolongs euphoric effect

Nicotine: stimulates release of dopamine (does not block reuptake)