The document discusses nociception and analgesics. It defines nociception as the neural processes involved in encoding and transmitting noxious stimuli via nociceptors. There are two types of axons - fast conducting Aδ fibers and slow C fibers. The body has an endogenous analgesia system supplemented by analgesic drugs which act on opioid receptors to reduce pain transmission. Morphine is a potent opioid analgesic that acts primarily on mu receptors, though it has various other pharmacological effects and side effects that require careful clinical use.

1. Analgesics

2. • Nociception (synonym: nocioception or
nociperception) is defined as "the neural processes of
encoding and processing noxious stimuli”. It is the
afferent activity produced in the peripheral and central
nervous system by stimuli that have the potential to
damage tissue.This activity is initiated by nociceptors,
(also called pain receptors), that can detect
mechanical, thermal or chemical changes above a set
threshold. Once stimulated, a nociceptor transmits a
signal along the spinal cord, to the brain. Nociception
triggers a variety of autonomic responses and may also
result in the experience of pain in human beings.[3]

3. • Nociceptors have two different types of axons. The first
are the Aδ fiber axons. They are myelinated and can
allow an action potential to travel at a rate of about 20
meters/second towards the CNS.
• The other type is the more slowly conducting C fiber
axons. These only conduct at speeds of around 2
meters/second.This is due to the light or non-
myelination of the axon. As a result, pain comes in two
phases. The first phase is mediated by the fast-
conducting Aδ fibers and the second part due to
(Polymodal) C fibers.

4. • The pain associated with the Aδ fibers can be
associated to an initial extremely sharp pain.
The second phase is a more prolonged and
slightly less intense feeling of pain as a result
from the damage. If there is massive or
prolonged input to a C fiber there is
progressive build up in the spinal cord dorsal
horn.

5. • The body possesses an endogenous analgesia
system, which can be supplemented with
analgesic drugs to regulate nociception and pain.
There is both an analgesia system in the central
nervous system and peripheral receptors that
decreases the grade in which nociception reaches
the higher brain areas. The degree of pain can be
modified by the periaqueductal gray before it
reaches the thalamus and consciousness.
According to gate control theory of pain, this area
can also reduce pain when non-painful stimuli are
received in conjunction with nociception

6. • Stimulation of the periaqueductal gray matter of the
midbrain activates enkephalin-releasing neurons that
project to the raphe nuclei in the brainstem. 5-HT
(serotonin) released from the raphe nuclei descends to
the dorsal horn of the spinal cord where it forms
excitatory connections with the "inhibitory
interneurons" located in the substantia gelatinosa.
When activated, these interneurons release either
enkephalin or dynorphin (endogenous opioid
neurotransmitters), which bind to mu opioid receptors
on the axons of incoming C and A-delta fibers carrying
pain signals from nociceptors activated in the
periphery.

7. • The activation of the mu-opioid receptor inhibits the
release of substance P from these incoming first-order
neurons and, in turn, inhibits the activation of the
second-order neuron that is responsible for
transmitting the pain signal up the spinothalamic tract
to the ventroposteriolateral nucleus (VPL) of the
thalamus. The nociceptive signal was inhibited before it
was able to reach the cortical areas that interpret the
signal as "pain" (such as the anterior cingulate). This is
sometimes referred to as the Gate control theory of
pain and is supported by the fact that electrical
stimulation of the PAG results in immediate and
profound analgesia.

11. Activation of nociceptors
• When nociceptors are stimulated they transmit signals
through sensory neurons in the spinal cord. These neurons
release the excitatory neurotransmitter glutamate at their
synapses.
• If the signals are sent to the reticular formation and
thalamus, the sensation of pain enters consciousness in a
dull poorly localized manner. From the thalamus, the signal
can travel to the somatosensory cortex in the cerebrum,
when the pain is experienced as localized and having more
specific qualities.
• Nociception can also cause generalized autonomic
responses before or without reaching consciousness to
cause pallor, diaphoresis, tachycardia, hypertension,
lightheadedness, nausea and fainting.

12. • Endorphins ("endogenous morphine") are
endogenous opioid peptides that function as
neurotransmitters. They are produced by the
pituitary gland and the hypothalamus in
vertebrates during exercise, excitement, pain
and they resemble the opiates in their abilities
to produce analgesia and a feeling of well-
being.

13. • Beta endorphin is released into blood from the pituitary gland and
into the spinal cord and brain from hypothalamic neurons. The β-
endorphin that is released into the blood cannot enter the brain in
large quantities because of the blood-brain barrier so the
physiological importance of the β-endorphin that can be measured
in the blood is far from clear. β-endorphin is a cleavage product of
pro-opiomelanocortin (POMC) which is also the precursor hormone
for adrenocorticotrophic hormone (ACTH). The behavioural effects
of β-endorphin are exerted by its actions in the brain and spinal
cord, and probably the hypothalamic neurons are the major source
of β-endorphin at these sites. In situations where the level of ACTH
is increased (e.g. Cushing’s Syndrome), the level of endorphins also
increases slightly.

14. OPIOID RECEPTORS
Receptor Subtypes Location Function
delta (δ)OP1
(I) δ1, δ2
 brain
 peripheral
sensory neurons
 analgesia
 antidepressant
effects
 physical
dependence
kappa (κ)
OP2
(I)
κ1, κ2, κ3
 brain
 spinal cord
 substantia
gelatinosa
 peripheral
sensory neurons
 analgesia
 sedation
 miosis
 inhibition of ADH
release
 dysphoria

15. mu
(μ)
OP3
(I)
μ1, μ2,
μ3
 brain
 spinal cord
o substantia gelatinosa
 peripheral sensory neurons
 intestinal tract
μ1:
 analgesia
 physical dependence
μ2:
 respiratory depression
 miosis
 euphoria
 reduced GI motility
 physical dependence
μ3:
 unknown

16. • β-endorphin has the highest affinity for the μ1 opioid receptor,
slightly lower affinity for the μ2 and δ opioid receptors and low
affinity for the κ1 opioid receptors. μ opioid receptors are the main
receptor through which morphine acts. Classically, μ opioid
receptors are presynaptic, and inhibit neurotransmitter release;
though through this mechanism, they inhibit the release of the
inhibitory neurotransmitter GABA, and disinhibit the dopamine
pathways, causing more dopamine to be released. By hijacking this
process, exogenous opioids cause inappropriate dopamine release,
and lead to aberrant synaptic plasticity, which causes addiction.
Opioid receptors have many other and more important roles in the
brain and periphery however, modulating pain, cardiac, gastric and
vascular function as well as possibly panic and satiation, and
receptors are often found at postsynaptic locations as well as
presynaptically.

17. ANALGESICS
• Analgesics are drugs that relieve pain without
significantly altering consciousness. They
relieve pain without affecting its cause

18. Analgesics
Opioid or Narcotic analgesics Non opioid or Non steroidal
anti-inflammatory drugs
OPIOIDS
Agonists Mixed agonists-antagonists Antagonists
(Buprenorphine, nalbuphine) (naloxone, naltrexone)
Strong Moderate weak
(Morphin, (codeine) (propoxyphene)
Methadone,
Meperidine)

19. CLASSIFICATION OF OPIOID
ANALGESICS
Strong Opioid agonists
• Natural opium alkaloids: Morphine, Methadone,
Fentanyl
• Partial agonists : Codeine, Hydrocodone
• Mixed opioid agonists- antagonist:
Buprennorphine, Nalbuphine
• Opioid antagonists: Naloxone, Naltrexone
• Other analgesics used in moderate pain:
Tramadol

20. MORPHINE
Opium the source of morphine obtained from Papaver somniferum and Papaver
album.
• Morphine and other opioids produce their actions by interacting with various
opioid receptors, mu, delta and kappa.
Pharmacological actions of Morphine
• Analgesic effect: mediated through mu receptors at spinal and supraspinal sites,
very potent analgesic, raises pain threshold, relieves dull as well as sharp pain.
• causes sedation and drowsiness
• euphoria
• respiratory depression
• cough suppression
• hypothermia
• Miosis
• Nausea and vomiting
• Stimulation of vagal centre

21. Other effects
• Physical and psychological dependence
• Histamine release causes skin rashes and urticaria, vasodilation,
bronchoconstriction.
• CVS: morphine causes bradycardia and fall in blood pressure. It
causes vasodilation of peripheral vessels.
• GIT: morphine causes constipation directly and CNS action
decreases GI motility and increases tone of sphincters
• Urinary bladder: morphine causes urinary retention by increasing
the tone of urethral sphincter
• Biliary tract: morphine increases the intrabiliary pressure.
• Bronchi: morphine causes bronchospasm by releasing histamine
from mast cells

22. Clinical use of morphine
• Analgesic: Pain associated with cancer is treated with
morphine
• Acute pulmonary edema and painful myocardial ischemia
• Pain associated with Chronic Pancreatitis
• pain in myocardial infarction
• pain in sickle cell crisis
• pain associated with surgical conditions, pre- and
postoperatively
• pain associated with trauma
• Pain from kidney stones (renal colic, ureterolithiasis)
• Severe back pain

23. Pharmacokinetics
• Morphine if given orally, undergoes extensive
first pass effect, hence oral bioavailaibility of
morphine is poor. It is commonly administered
by i.v or i.m routes. It is widely distributed in
body. In liver it is metabolized by glucuronide
conjugation. Morphine-6- glucuronide has
more potent analgesic action than morphine
and is excreted in urine

24. Adverse Effects
• Nausea, vomiting and constipation.
• Respiratory depression
• Hypotension due to vasodilation
• Drowsiness and confusion
• Itching , skin rashes
• Difficulty in micturation
• Drug tolerance develops to most effects of
morphine except miotic and constipating effects.
There is cross tolerance among the opioids.

25. • Tolerance and Drug dependence is the main drawback of the
therapy. Physical dependence is associated with the development
of abstienence syndrome. The signs and symptoms are abnormal
behavior such as irritability, body shakes and other symptoms like
yawning, lacrimation, sweating, fever, diarrhea, mydriasis,
palpitation, insomnia, rise in B.P, loss of weight. Dependence is
mediated through mu receptors.
• Treatment of morphine dependence
• Hospitalization of the patient
• Gradual withdrawal of morphine
• Substitution therapy with methadone
• Opioid antagonist like naltrexone is used for detoxification and
produce opioid blockade. It is preffered antagonist and has long
duration of action.

26. Acute morphine poisoning
• Symptoms of morphine poisoning include respiratory
depression, pinpoint pupils and coma. Other symptoms
are cyanosis, hypotension, shock and convulsions.
Death is usually due to respiratory depression.
• Treatment
• Hospitalization
• Maintain airway breathing and circulation.
• Gastric lavage with potassium permanganate.
• Specific antidote: Naloxone, 0.4-0.8 mg i.v, dose is
repeated until respiration becomes normal

27. Contraindictions
• Head injury: Morphine is contraindicated in cases with head injury
because:
• Vomiting and miosis produced by morphine
• morphine Respiratory depression CO2 retention
cerebral vasodilation Increased intracranial pressure
• Bronchial Asthma: morphine may precipitate an attack by histamine
release
• Chronic obstructive pulmonary disease (COPD)
• Hypotensive states
• Hypothyroidism
• Infants and old people
• Undiagnosed acute abdominal pain

28. Drug Interactions
• Sedative – hypnotics
• Antipsychotic traquilizers
• Monoamine oxidase inhibitors