By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 3

PEPTIDE NEUROTRANSMITTERS

Developments beyond cholinergic and NA transmission

• Quick revision:
• Noradrenaline is stored in vesicles, together with:
• ATP
• Neuropeptide Y
• Chromogranins
• ATP is though to be involved in keeping NA in the vesicle, and may have some transmitter effect.
• Neuropeptide Y, on its own, is not a good vasoconstrictor, but it markedly enhances vasoconstriction by
noradrenaline

• In the parasympathetic system, Ach is also stored in vesicles in conjunction with other chemicals:
• Vasoactive intestinal peptide (VIP)
• This chemical is especially present in parasympathetic nerves innervating the salivary
glands.
• It does little on its own, but when used in conjunction with Ach, markedly increases
salivary secretion.
• Hence, these other peptide neurotransmitters may be acting as modulators.

Substance P
• This was the first peptide neurotransmitter discovered
• Peptide neurotransmitters seem to exist in a wider family of peptides.
• Substance P belongs to a peptide family known as tachykinins
• Other members of the tachykinin family are neurokinin A and B

Tachykinins
• Synthesis:
• Because these chemicals are peptides, they are synthesised by genetic transcription and translation.
Hence, their synthesis may take hours.
• There are 2 genes involved in the synthesis of tachykinins:
• Gene 1
• Transcription and translation produces 3 precursor proteins. These precursor proteins
undergo postranslational modification to form either substance P or NKA
• α preprotachykinin A
• Substance P
• β preprotachykinin A
• Substance P
• NKA
• γ preprotachykinin A
• Substance P
• NKA
• Gene 2
• Same thing occurs as for gene 1:
• preprotachykinin B
• Neurokinin B

• The nerves which have these genes are found in:

• The CNS (mainly in areas involved in motor function)
• In peripheral nerve fibres
• Mainly in nociceptive fibres and enteric nerves

Actions of substance P
• Contracts the gut and bronchi
• Substance P containing nerves control peristalsis and asthma
• Stimulates cutaneous pain receptors
• It is the transmitter used in primary afferent sensory fibres
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 3

• Relaxes vascular smooth muscle (probably via NO released from endothelial cells)
• Lowers blood pressure if injected intravenously
• Axon reflex in the triple response
• Increases vascular permeability Seems to be involved in the inflammatory process
• Dilation of cerebral vessels (migraine?)
• Histamine release, exocrine secretions:
• Diuresis
• Lacrimation
• Salivation

Substance P receptors

Receptor Agonist
NK1 Substance P
NK2 NKA
NK3 NKB
• Antagonist:
• The only important one is spantide which inhibits NK1 receptor
• Can be injected intrathecally to people with chronic back pain. Since substance P seems to be
the transmitter in the primary sensory afferent fibres involved in pain, blocking its effects can be
used to relieve pain.
• Other possible uses:
• Analgesics, asthma, headaches
• Since all these chemicals are peptides, they cannot be given orally, since they will be digested by the enzymes in
the gut.

Drug acting on the storage of substance P

• Capraicin
• Found in capraicin spray, chilli peppers
• Causes release of SP from sensory fibres, resulting in painful sensations, flushing, stinging, watery eyes
and salivation (all the effects of substance P) - To remember the actions of substance P, recall what it is
like to eat a chilli pepper!
• Continual stimulation can deplete stores (since it takes a long time to make new substance P)
• Used clinically for people with herpes lesions on the skin, which are extremely painful. When given, it
will cause an initial increase in SP release, but since the people are experiencing pain already, they won't
notice. When SP has been depleted, the people will get relief.

Inactivation of substance P
• Peptidyl dipeptidase
• Maybe angiotensin converting enzyme

Endogenous opiods
• Endogenous opioids are endogenous pain modulators
• Morphine is an opiate analgesic, obtained from the opium poppy
• The effects of morphine can be antagonised by naloxone.
• Certain pentapeptides (met-enchephalin, leu-encephalin) found in the brain are found to be agonists of the binding
site of morphine. These peptides may be the body's natural opiods.

Endorphins
• A generic term comprising of a family of peptides derived from 3 distinct precursors
• Terminology:
• Opiates: Synthetic morphine analogues
• Opiods: Morphine analogues which includes the peptides
• Endorphins: A general family derived from 3 distinct precursors.

Synthesis of endogenous opiods

• 1st precursor
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 3

• Preproopiomelanocortin
• Located mainly in the pituitary gland (and hypothalamus)
• Can produce:
• Melanocyte stimulating hormone
• ACTH
• β endorphin
• β lipotropin
• met and leu encephalin are present in the precursor protein but there is no evidence
that they are released. The main one is beta endorphin
• 2nd precursor
• Preproencephalin
• Found in the CNS, spinal cord, GIT and adrenals
• Can produce:
• Met and leu enchephalin
• 3rd precursor
• Preprodynorphin
• Found in CNS, GIT and pituitary
• Produces dynorphin A

Actions of opiods
1. Analgesia
• Supraspinal analgesia
• Can feel pain but not disturbed by the pain
• Spinal analgesia
• Can prevent transmission of the pain (may inhibit the transmission of substance P)
2. Psychotropic
• Euphoria
• Sedation Whether euphoric or not depends on the concentration
• Dependence
3. GIT
• Constipation (may inhibit substance P which causes GIT motility)
4. Respiration
• Respiratory depression
5. Decreases the excitability of other neurons by opening K+ channels, hyperpolarising the membrane. This limits
Ca2+ entry, hence the nerve can't release transmitter.

Endogenous opiod receptors

• µ beta endorphin, met-encephalin
• δ leu-encephalin
• κ dynorphin
• σ No longer considered an opiod receptor since it can be activated by other, non opiod substances,
e.g. phencyclidine (angel dust), haloperidol (dopamine agonist)

• Morphine tends to show µreceptor selectivity

• Antagonists: Naloxone

Roles of opiods
• Pain modulation
• Affects how the body senses and reacts to pain
• Released during acupuncture
• Released during marathons so runners can cope with the pain
• Side effects
• Decrease in gut motility, causing constipation

• All these effects may be due to inhibiting the release of substance P