Chapter 2. Pain Physiology Flashcards

Question

70. Neurotransmitters in the central nervous system (CNS) are classified into which of the following? (1) Excitatory (2) Inhibitory (3) Neuropeptides (4) Regulatory

Answer 1

70. (A) There are three main classes of neurotransmitters; excitatory, inhibitory, and neuropeptides. Tissue injury results in the local release of numerous chemicals which either directly induce pain transduction by activating nociceptors or facilitate pain transduction by increasing the excitability of nociceptors. There are three classes of transmitter compounds; excitatory neurotransmitters, inhibitory neurotransmitters, and neuropeptides, that are found in three anatomical compartments; sensory afferent terminals, local circuit terminals, and descending (or ascending) modulatory circuit terminals.

Answer 2

71. (B) Glutamate and aspartate are the main excitatory neurotransmitters, whereas GABA and glycine are inhibitory neurotransmitters.

Answer 3

72. (B) NMDAreceptor activation causes increased pain transmission whereas its blockade attenuates pain transmission. There are four receptor types for glutamate and aspartate in the somatosensory system. The class of receptors best activated by NMDA is termed the NMDA receptor. The NMDAreceptor is usually considered as recruited only by intense and/or prolonged somatosensory stimuli. This characteristic is due to the NMDAreceptor’s well-known magnesium block that is only relieved by prolonged depolarization of the cell membrane.

Answer 4

73. (C) NMDA receptors are critically involved in the induction and maintenance of neuronal hyperexcitability after noxious events. Until recently, only central NMDA receptors were a primary focus of investigations. With the recognition of peripheral somatic and visceral NMDA receptors, it is now apparent that the role of NMDA receptors in pain is much greater than thought previously. Over the past decade, accumulating evidence has suggested that the NR2B subunit of NMDA receptor is particularly important for pain perception. Given the small side-effect profile and good efficacy of NR2Bselective compounds, it is conceivable that NR2B-selective blockade will emerge as a viable strategy for pharmacological treatment of pain.

Answer 5

74. (D) Both are clinically used NMDA receptor blockers, causing analgesia. Clinically available compounds that are demonstrated to have NMDA receptor-blocking properties include ketamine, dextromethorphan, and memantine. Dextromethorphan, for example, is effective in the treatment of painful diabetic neuropathy and not effective in postherpetic neuralgia and central pain. NMDA receptor blockers may therefore offer new options in the treatment of pain.

Answer 6

75. (C) Nitric oxide is released in response to NMDAreceptor activation and is implicated in neuronal plasticity rather than antinociception. Amongst the substances found in the descending inhibitory pathways of the CNS are norepinephrine and serotonin.

Answer 7

76. (D) The Ca2+ channel can be divided into subtypes according to electrophysiological characteristics, and each subtype has its own gene. The L-type Ca2+ channel is the target of a large number of clinically important drugs, especially dihydropyridine, and binding sites of Ca2+ antagonists have been clarified. N-type calcium channels are primary targets for the calcium channel blockers with analgesic properties. The N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions.

Answer 8

77. (B) N-type channels are highly concentrated in both DRG cell bodies and also in the synaptic terminals they make in dorsal horn of the spinal cord (laminae L1 and L2). Commonly they are found in presynaptic terminals. Critically, block of N-type currents inhibits the release of neuropeptides substance P and calcitonin generelated peptide (CGRP) from sensory neurons.

Answer 9

78. (D) Windup refers to the progressive increase in the magnitude of C-fiber evoked responses of dorsal horn neurons produced by repetitive activation of C-fibers. Neuronal events leading to windup also produce some of the classical characteristics of central sensitization including expansion of receptive fields and enhanced responses to C but not A δ-fiber stimulation.

Answer 10

79. (B) Primary inhibitory neurotransmitters of the somatosensory system include the amino acids glycine and GABA. Glycine is particularly important at spinal levels, while GABA is the chief inhibitory transmitter at higher levels. Three types of GABA receptors have been identified. GABAA receptor is linked with a chloride channel and modulated by barbiturates, benzodiazepines, and alcohol. Selective GABAA agonists include muscimol and selective antagonists include gabazine. The GABAB receptor has been associated with both a potassium ionophore and G protein-linked complex. Baclofen is a selective GABAB receptor agonist and phaclofen is a selective antagonist. Finally the newly described GABAC receptor has also been described as associated with a potassium channel ionophore. Glutamate and aspartate are excitatory neurotransmitters.

Answer 11

80. (B) The excitatory neuropeptides in the somatosensory system include substance P and neurokinin A. These peptides are especially concentrated in primary afferent fibers but also present in intrinsic neurons of the spinal dorsal horn and thalamus. The inhibitory neuropeptides at spinal levels include somatostatin, the enkephalins, and possibly dynorphin. These peptides are contained in both intrinsic neurons of the dorsal horn and in the fibers descending to the dorsal horn from various brainstem nuclei.

Answer 12

81. (B) Serotonin is one of many mediators that are released from platelets (rats and humans) and mast cells (rats) in injured and inflamed tissues. In situ hybridization, studies have shown that DRG neurons normally express mRNA for 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT3B, and 5-HT4 receptors. Many of the excitatory actions of serotonin have been ascribed to the ligandgated 5-HT3 receptor, but there is good evidence that serotonin can activate and sensitize nociceptors by actions on G protein–coupled receptors. 5-HT2 receptors are expressed largely in (calcitonin gene-related peptide) CGRPcontaining, small-diameter sensory neurons, and their activation produces thermal hyperalgesia. 5-HT2 receptors are usually linked to the phospholipase C pathway. Activation of 5-HT2 receptors depolarizes capsaicin-sensitive DRG neurons by reducing a resting potassium potential, and such an effect could contribute to both excitation and sensitization.

Answer 13

82. (E) Four types of G protein–coupled PARs have been identified (PAR1-PAR4). These receptors are activated by a unique mechanism whereby extracellular, soluble, or surface-associated proteases cleave at specific residues in the extracellular N-terminal domain of the G protein to expose a novel N-terminal sequence, which acts as a tethered ligand that activates the receptor by binding to other regions of the protein. These agonist effects can be mimicked by short synthetic peptides based on the sequence of the tethered ligands of the different PARs. PAR1, PAR2, and PAR4 are activated by thrombin produced during the blood-clotting cascade, while PAR3 activation is triggered by tryptase, which is known to be released from mast cells in inflammatory conditions, as well as the blood-clotting factors VIIa and Xa. In this way, PARs are activated as a result of tissue damage and inflammation. Because activation involves an irreversible enzymatic cleavage, restoration of PAR sensitivity requires internalization of the receptors and insertion of new receptor into the plasma membrane. PARs were initially detected in platelets, endothelial cells, and fibroblasts, but are now known to also be expressed in the nervous system. PAR1 and PAR2 are expressed on peripheral sensory neurons. PAR2 is expressed in about 60% of rat DRG neurons, where it is found mainly in the small to medium-sized neurons, with a significant number coexpressing substance P and CGRP.

Answer 14

83. (E) NGF levels increase during inflammation. NGF is a critical mediator of inflammatory pain. NGF clearly has a powerful neuroprotective effect on small-diameter sensory neurons, and NGF levels have been shown to change in a number of models of nerve injury. However, its exact role in the development of neuropathic pain is at present unclear. Blocking NGF bioactivity (either systemically or locally) largely blocks the effects of inflammation on sensory nerve function. Elevated NGF levels have been found in a variety of inflammatory states in humans, including in the bladder of patients with cystitis, and there are increased levels in synovial fluid from patients with arthritis.

Answer 15

84. (E) The contribution of endogenous opioid peptides to pain modulation was first suggested by reports that stimulation-produced analgesia in animals and humans is reduced by the narcotic antagonist naloxone. Naloxone also worsens postoperative pain in patients who have not received exogenous opioid therapy, thus establishing the relevance of endogenous opioids to common clinical situations. Peptide transmitters and hormones are derived by the cleavage of larger, usually inactive, precursor. Met- and leu-enkephalin are derived from a common precursor, preproenkephalin, each molecule of which generates multiple copies of met-enkephalin and one of leuenkephalin. β-Endorphin is cleaved from a larger precursor protein, proopiomelanocortin, which also gives rise to adrenocorticotrophic hormone and several copies of melanocytestimulating hormone. Two copies of dynorphin (A and B) and α-neoendorphin are generated from a third endogenous opioid precursor molecule (preprodynorphin).

Answer 16

85. (F) Nociceptors are free nerve endings and do not have any specific receptors, but are activated by a tissue injury due to mechanical, thermal, or chemical stimuli.

Answer 17

86. (T) “A-δ” fibers are myelinated fibers and conduct the impulses faster (5-20 m/s) than the C fibers, which are unmyelinated (

Answer 18

87. (T) WDR neurons respond to nociceptive as well as nonnociceptive stimuli transmitted by the peripheral nerves. These types of receptors are located in the dorsal horn of the spinal grey matter

Answer 19

88. (F) Visceral pain is usually felt as referred pain. This type of pain can be “with hyperalgesia” or “without hyperalgesia.” Most structures elicit a midline or bilateral pain; however, certain structures such as kidneys and ureters can produce unilateral pain. Referred pain with hyperalgesia is termed “true parietal” pain and usually extends to the muscles, but can extend up to the skin

Answer 20

89. (T) NMDAreceptors are involved in the induction and maintenance of certain pathological pain states produced by peripheral nerve injury, possibly by sensitizing dorsal horn neurons. These receptors have been implicated in the phenomenon of windup and related changes such as spinal hyperexcitability that enhance and prolong sensory transmission

Answer 21

90. (F) There are multiple neuropeptides that contribute to signaling of somatosensory information. Some of these could be classified as excitatory compounds and others as inhibitory. Neuropeptides tend to have more gradual onset of effects as well as much more prolonged duration of action once released.

Chapter 2. Pain Physiology Flashcards

(45 cards)