PHYSIOLOGY, MECHANISMS, BIOCHEMISTRY & MANAGEMENT- by wurl boss Neil Barry

ALL ABOUT BEADS PAIN

› BEFORE

› EFFERENTS

› AFFERENTS

› DESENSITIZE

B.E.A.DS.

› Don’t be appalled. We got this.

› Nociceptors

› Dorsal Horn

› Dorsal root ganglia

› Afferent neurons

› Opioids

› Ischemia

› Prostaglandins

› Bradykinins

› Mu, delta, kappa

KEY TERMS

› NEURAL MECHANISMS– CHEMICAL MEDIATORS

› NEUROTRANSMITTERTS IN THE NOCICEPTIVE PATHWAY– OPIOIDS

› MORPHINE› TOLERANCE› DEPENDENCE

PHSIOLOGY OF PAIN

WHAT IS PAIN AND HOW DO WE STUDY IT?› PAIN IS A DIRECT RESPONSE TO SOME EVENT THAT PRODUCES

TISSUE DAMAGE

› COMMON TESTS INCLUDE:

› APPLYING A NOXIOUS STIMULES TO AN ANIMAL, LOOKING FOR THE RESPONSE E.G.

› MEASURING THE TIME IT TAKES FOR A RODENT TO WITHDRAW ITS TAIL WHEN EXPOSED TO HEAT

› Tissue injury results in local release of several chemicals that stimulate afferent receptors and neurons

› Excitatory amino acids and neuropeptides act as transmitters between primary afferents and spinal cord NCNs.

NEURAL MECHANISMS OF PAIN

› NCN: unmyelated C fibers and finely myelated A fibers that respond to mechanical, thermal, or chemical stimuli.

› A fibers Produce sharp, intense, and well localized discomfort.

› C fibers produce dull, burning type pain

› Two mechanisms may be involved with pain production :

› Nociceptive afferent neurons (NCN) and

› Abnormal central control over the afferent input

NEURAL MECHANISMS OF PAIN

› In the dorsal horn, nociceptive block is attained by ‘N-methyl-D-asparate’ (NMDA) blockers, by antagonists of ‘substance P’, and by inhibitors of nitric oxide synthesis.

NEURAL MECHANISMS OF PAIN› Substance P is an excitatory

transmitter which produces a slow depolarizing response in the postsynaptic cell that increases in amplitude with repetitive stimulation.

› P also enhances NMDA receptor transmission, enhancing pain perception, and produces inflammation.

› The Vanilloid Receptor: binds to a receptor, opening up an ion channel permeable to several cations, initiating an action potential.

› Hydrogen and heat produce a similar response.

› Chemicals in response to perceptive changes are released as a result of inflammatory or ischemic changes in tissues

Chemical Mediators of Pain

› Prostaglandins:

› Released during inflammatory states and during ischemia

› Do not produce pain, but enhance the pain producing effects of serotonin and bradykinin.

› Aspirin type drugs help reduce this pain, by inhibiting prostaglandins.

› Bradykinin:

› Becomes more potent in the presence of prostaglandins.

› Usually coupled with the activation of vanilloid receptor channel.

› Other examples: serotonin, histamine, lactic acid, adenosine triphosphate, and potassium.

Chemical Mediators of Pain

› The presynaptic action of opioids to inhibit neurotransmitter release is considered to be their major effect in the nervous system.

› Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes.

Opioids

› Diagram of human m opioid receptor. Chains of amino acids are shown as black lines. The 7 transmembrane -spanning domains (each containing 20 or more amino acids) are shown as cylinders.

Opioids

› The opioid receptors and many other membrane receptors are coupled to guanine nucleotide binding proteins known as G-proteins. G-proteins consist of 3 subunits (a, b and g). When the receptor is occupied, the a subunit is uncoupled and forms a complex which interacts with cellular systems to produce an effect

Opioids

› Additionally, the final effect of an opioid in the brain is the result, not only of its action at multiple presynaptic sites on both inhibitory and excitatory neurons, but also of its postsynaptic effects

› Opioids have actions at two sites, the presynaptic nerve terminal and the postsynaptic neuron.

› The presynaptic action of opioids is to inhibit neurotransmitter release, and this is considered to be their major effect in the nervous system

Sites of action of opioids on neurons

› Morphine, by an action on m receptors, inhibits release of several different neurotransmitters including

› noradrenaline,

› acetylcholine

› and the neuropeptide, substance P.

Examples

› The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain.

› Primary sensory neurons involved in pain sensation release predominantly substance P and glutamate in the dorsal horn of the spinal cord.

› Nociceptive information is transmitted to the brain via the spinothalamic tracts.

› This ascending information can activate descending pathways, from the midbrain periaqueductal grey area,

› which exert an inhibitory control over the dorsal horn.

Opioids and pain pathways

› Drugs may inhibit neurotransmitter release by a direct effect on Ca++ channels to reduce Ca ++ entry, or indirectly by increasing the outward K + current, thus shortening repolarisation time and the duration of the action potential.

› Neurotransmitter release from neurons is normally preceded by depolarisation of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels.

Opioid inhibition of neurotransmitter releasese

› Opioids produce both of those effects because opioid receptors are coupled via G-proteins directly to K+ channels and voltage-sensitive Ca++ channels. Opioids also interact with other intracellular effector mechanisms, the most important being the adenylate cyclase system

Opioids

› Decreased Ca++ entry

› Increased outward movement of K+

› Inhibition of adenylate cyclase

Points to Note

› Tolerance is mainly due to receptor desensitisation induced by functional uncoupling of opioid receptors from G-proteins, thus uncoupling the receptors from their effector systems

› Tolerance and dependence are induced by chronic exposure to morphine and other opioids more than any other group of drugs.

› Tolerance means that higher doses of opioids are required to produce an effect. When the degree of tolerance is very marked, the maximum response attainable with the opioid is also reduced

Tolerance and dependence:

› Dependence occurs much more rapidly than tolerance, and naloxone-precipitated withdrawal can be seen after a single dose of morphine in humans.

› Although dependence usually accompanies tolerance, they are distinct phenomena.

› Dependence is masked until the opioid drug is removed from its receptors, either by stopping the drug or by giving an opioid receptor antagonist such as naloxone.

› A withdrawal or abstinence response then occurs.

Dependence

› 2. Naloxone is a partial agonist because it only acts at one type of opioid receptor.

› False

› 1. Presynaptic inhibition of neurotransmitter release by morphine may cause an excitatory effect.

› True

The following statements are either true or false

› Gladson, Barbera. Pharmacology for Physical Therapists. Newark. Vol 1. 179-184

› Akil H, Simon EJ, editors. Opioids I and II. Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1993; vol. 104.

› Reisine T, Bell GI. Molecular biology of opioid receptors. Trends Neurosci 1993;16:506-10.

› Dickenson AH. Where and how do opioids act? Proceedings of the 7th World Congress on Pain. In: Gebhart GF, Hammond DL, Jensen TS, editors. Progress in pain research and management, Vol. 2. Seattle: IASP Press, 1994:525-52.

References