Analgesic pathways and referred pain

Analgesic pathways of brain and spinal cord and referred pain

1. Analgesic pathways of brain and spinal cord and referred pain By Amrutha Sivakumar

2. What is pain? It is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage It is given by International Association of Study of Pain (IASP)

3. What is an analgesia? Absence of sensibility to pain, particularly the relief of pain without loss of consciousness is called ANALGESIA . Results from an interruption in the nervous system pathway between sense organ and brain.

4. WHAT is an analgesic system? It is a pain control system that is activated by the brain to suppress input of pain signals to the nervous system. It consists of 3 major components in brain and spinal cord: The periaqueductal gray and periventricular areas. The raphe magnus nucleus and nucleus reticularis paragigantocellularis. Pain inhibitory complex present in dorsal horns of spinal cord.

5. Periaqueductal gray and periventricular areas of mesencephalon and upper pons Surrounds the Aqueduct of Sylv ius and portions of third and fourth ventricles Neurons send signals Raphe magnus nucleus – located in lower pons and upper medulla & Nucleus reticularis paragigantocellularis – located laterally in medulla Dorsolateral Columns in the Spinal Cord Second order signals Pain inhibitory complex located in the dorsal horns of spinal cord Analgesia signals block the pain before it is relayed to the brain

6. Stimuli which excite analgesic pathways: Electrical stimulation either in the periaqueductal gray area or in the raphe magnus nucleus can suppress many strong pain signals entering by way of dorsal spinal roots. Stimulation of areas at still higher levels of brain that excite the periaqueductal gray area can suppress pain. Periventricular nuclei in the Hypothalamus Medial forebrain bundle in the hypothalamus

7. Stimulation produced analgesia: SEGMENTAL INHIBITION Stimulation of nerves in the same segment in which pain is felt can relieve such pain. Achieved by: Activation of group A afferent fibers Stimulation of dorsal column of spinal cord which in turn activates segmental collaterals – GATE CONTROL THEORY OF PAIN (MELZACK AND WALL) SUPRASPINAL INHIBITION A descending inhibitory pathway from the brain stem to Rexed laminae I, IV & V can also produce analgesia. E.g., Mesencephalic pain inhibitory pathway Arises from midbrain and descends to dorsal horn cells, in spinal cord. Contains opiate receptors. Stimulated in: Structures immediately surrounding III ventricle Periaqueductal grey matter in mid brain Substantia nigra of basal ganglia Nucleus raphe magnus

8. REXED LAMINAE Rexed's laminae is an architectural classification of the structure of the spinal cord, based on the cytological features of the neurons in different regions of the gray substance described by the Swedish Anatomist B. Rexed . A system of ten layers of grey matter (I–X) Used to label portions of the grey columns of the spinal cord .

9. Gate control theory Pain can be modulated by the peripheral mechanisms, especially by gating the impulses in the spinal cord . Collaterals from large myelinated afferent fibres associated with tactile sensibility produce presynaptic inhibition of A∂ and C fibers in the dorsal horn of spinal cord. Thus activity in the large afferent fibers regulates the transmission of impulses originating in the pain receptors.

10. Touching or Shaking an injured area, decreases the pain of injury. Why does rubbing over a painful area in the body help reduce discomfort?

11. Back in the 17th century , the prevailing explanation of pain was mostly concerned with the Specificity Theory of pain . According to this theory, the experience of pain was believed to be directly and linearly related to the injury, because pain impulses (from the affected region) travelled directly to the brain. In the year 1965 , Ronald Melzack and Patrick Wall proposed the Gate Control Theory of pain, which introduced the world to a whole new perspective on pain perception.

12. According to the Gate Control Theory of pain, the pain signal is transmitted from the peripheral nervous system to the central nervous system. The pain signal is modulated in the central nervous system (in the dorsal horn of the spinal cord) by a gating system, and then transmitted to the brain, which finally ‘perceives’ it. The perception of pain by the brain can be influenced (i.e., increased or decreased) if the gating system is impacted. gating system can be impacted in two main ways; The first relates to descending nerve impulses from the brain that mess with the ascending pain impulses from the affected area. These descending impulses may include cognitive, emotional or psychological factors, such as beliefs, memories, cultural attitudes, or memories of a prior experience in a similar situation.

13. The other way of influencing the perception of pain is to receive ascending signals from peripheral nerves , which represent competing sensory information and mess with the way your brain perceives pain. The practice of ‘ rubbing something better ’ falls in this category.

14. Suppose you hit your elbow on the edge of a table.

15. Instantly, pain signals from your elbow travel to the brain, but when you do something else to your elbow, like rub or shake it , other sensory signals are fired from the same part of your body, also racing to reach the brain. When multiple signals emanating from the same part of the body try to reach the brain, the aforementioned gating mechanism only allows one signal at a time to actually reach the brain. It so happens that stimuli like touch , vibration and pressure get preferential treatment over pain signals .

16. Rubbing/shaking an affected body part causes other receptors to fire and, in a bid to be perceived, they overload the brain . By doing that, they prevent  pain signals from being appropriately perceived by the brain. That’s the reason why the age-old method of “rubbing it better” always seems to work, at least to a certain extent.

17. ENDOGENOUS OPIOD SYSTEMS Morphine is a potent endogenous analgesic peptide . It acts at synapses of nociceptive pathways by binding to specific sites – Opiate receptors The binding of morphine molecules to an opiate receptor decreases nociceptive synaptic excitability. There are 3 major classes of opiate receptors: µ ∂ 𝛋 Genes encoding these receptors are found to be members of G protein – coupled class of receptors. Morphine is a potent agonist of the µ receptor.

18. Opiates such as morphine act presynaptically and postsynaptically to inhibit the transmission of impulses from A∂ and C fibers. Increased potassium conductance of postsynaptic membrane produces postsynaptic inhibition and inhibition of release of substance P from the terminals of sensory neurons results in presynaptic inhibition . These effects are reversed by naloxone , the narcotic antagonist that binds to µ receptor. Substance P is a peptide containing 11 amino acids and is a mediator of pain. Its release from primary afferent nerve endings is brought by neuronal stimulation of afferent A∂ and C group fibers in peripheral nerves.

19. There are many opioid peptides synthesized endogenously in our body. These are collectively known as endorphins (endogenous morphine like substances) The important endorphins are: Enkephalins: Leu-enkephalins Met-enkephalins β – endorphin Ɣ – endorphin Dynorphin α – neoendorphins The endorphin receptors are particularly present in spinal cord , Periaqueductal gray of midbrain, and raphe nucleus in medulla. Endorphins produce profound analgesia when they are secreted from different parts of brain in response to different stimuli.

20. Clinical applications Soldiers wounded in the heat of battle may feel no pain until the battle is over. This is called Stress Analgesia During stress, reaction of the individual to pain is suppressed. This results in analgesia. Stress induced analgesia occurs by both opioid and non opioid mechanisms, Stress activates descending analgesia systems: Descending Raphespinal Serotonergic Pathway Descending Ceruleospinal Norepinephrinergic Pathway

21. Substantia Nigra ( Dopaminergic pathway ) Periaqueductal Grey Matter ( Serotonin – 5 HT containing pathway ) Raphe Nucleus Spinal Cord Rexed Laminae I, IV & V

22. Acupuncture It is often used to relieve pain. In acupuncture, needle - puncture is made at a distant but specific location from the site of pain. Analgesia in this method occurs by mechanisms: Release of endorphins Gate control mechanism Counterirritants i.e., stimulation of skin over an area of visceral inflammation produces some relief of the pain due to visceral disease. Trans Cutaneous Electrical Nerve Stimulation (TENS) Often used in lessening pain The pain sites itself or the nerves leading from it are stimulated by electrodes placed on the surface of skin . It works because the stimulation of non – pain , low – threshold afferent fibers such as the fibers from the touch receptors leads to inhibition of neurons in the pain pathways.

23. Placebos A pharmacologically inactive substance administered as a drug Capable of producing the release of endogenous opioids and thus help in relieving pain

24. What is referred pain? When the sensation of pain is experienced at a site other than the injured or diseased part, it is called referred pain. When the pain seems to spread from the local area to distant area, it is called radiating pain .

25. Examples of referred pain Phantom limb pain Pain of stone in the gall bladder referred to tip of right shoulder Pain in testicles due to stone in ureter During a heart attack , pain is experienced at the tip of left shoulder and tends to spread in the inner aspect of the left arm .

26. Cause of referred pain Pain is usually referred to a structure that developed from the same segment during the embryonic development. This principle is called the dermatomal rule. For e.g., The heart and the arm have the same segmental origin The testicles and kidney developed from the same primitive urogenital ridge.

27. Mechanism of referred pain Branches of visceral pain fibers synapse in the spinal cord on the same second – order neurons that receive pain signals from the skin. When the visceral pain fibers are stimulated, pain signals from the viscera are conducted through at least some of the same neurons that conduct pain signals from the skin, and the person has the feeling that the sensations originate in the skin .

28. Convergence theory The nerves from the visceral structures and somatic structures to which pain is referred, enter the CNS at the same level and converge on the same spinothalamic neurons . Since somatic pain is far more common than visceral pain , therefore, when the same afferent pathway is stimulated by signals that originate in visceral afferent nerves, the signal that reaches the somatosensory cortex is identical and is misinterpreted as having arisen within the somatic area.

29. Facilitation theory The afferent impulses from the visceral structures produce subliminal fringe effects that lower the excitability threshold of spino thalamic neurons which receive afferent fibers from somatic areas. Postsynaptic neurons are said to be in a subliminal fringe if they are not discharged by activity in the presynaptic neurons but do have their excitability increased. Therefore, any slight activity in the pathways transmitting pain impulses from somatic regions, and which normally would die out within the spinal cord, is facilitated and thus reaches conscious levels .

30. References: Guyton & Hall G.K. Pal A.K. Jain