Anti-NGF

Question 1

NGF was the first neurotrophic factor to be

Answer 1

discovered and purified

Question 2

TrkA mediates

Answer 2

the survival-promoting and neurite-growth-promoting effects of NGF during development and its later pain-provoking actions

Question 3

Adaptor proteins include

Answer 3

Shc, phospholipase Cγ (PLC-γ) and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2)

Question 4

intracellular signalling pathways include

Answer 4

Mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and PLC pathways

Question 5

NGF–trkA signalling complex is retrogradely transported in signalling endosomes together with proteins of

Answer 5

the p38 MAPK, extracellular-signal-regulated kinases (ERK1 and ERK2) and PI3K pathways along peripheral nerves to the cell bodies of nociceptive neurons

Question 6

Retrograde signalling regulates

Answer 6

the activity of several transcription factors, such as c-FOS, c-JUN and forkhead-1, which leads to alterations in gene expression

Question 7

In animal studies, the concentration of NGF in the skin increases in response to

Answer 7

inflammation produced by either injection of irritants (Oddiah et al.,1998) or ultraviolet-B irradiation (Woolf et al.,1994)

Question 8

In rodents, NGF causes robust, long-lasting

Answer 8

mechanical and thermal hyperalgesia (an exaggerated response to painful stimuli) following either local or systemic administration (Lewin et al., 1994) (Della Setta et al., 1994)

Question 9

In humans, subcutaneous

Answer 9

injection of NGF into the forearm of healthy volunteers produced allodynia (pain from innocuous stimuli) and hypersensitivity in the surrounding skin that lasted for up to three weeks (Dyck et al., 1997)

Question 10

In a controlled trial of the effects of NGF injection into the masseter muscle of healthy volunteers,

Answer 10

local mechanical allodynia and hyperalgesia were observed for at least a week, and pain was observed during strenuous jaw movement (Svensson et al.,2003)

Question 11

Direct administration of NGF into the sciatic nerve

Answer 11

also produces hyperalgesia (Ruiz et al.,2004).

Question 12

NGF sensitizes nociceptive neurons directly to

Answer 12

several pain-provoking stimuli by causing rapid post-translational changes in the transient receptor potential vanilloid receptor 1 (TRPV1) cation channel and by modulating the expression of genes that influence nociceptor function

Question 13

Studies using pharmacological inhibitors in polymodal nociceptors…

Answer 13

(for example, Zhuang et al., 2004), indicate that the PI3K pathway is crucial for mediating sensitization to NGF, with both Ca2+–calmodulin-dependent kinase II and protein kinase C (PKC) acting downstream of PI3K.

Question 14

______sensitizes TRPV1 by direct phosphorylation

Answer 14

PKC-ε

Question 15

Retrograde NGF signalling from

Answer 15

the peripheral terminals to the cell bodies of nociceptive neurons enhances the expression of several proteins that further sensitize these neurons and facilitate activation of second-order neurons in the CNS.

Question 16

Blocking NGF markedly reduces hyperalgesia and pain in animal models of many pain states. State 2 animal studies.

Answer 16

1. In a model of postoperative pain that involves making an incision through the skin and plantar muscles of the rat hindpaw followed by closure with sutures, blocking the function of NGF reduces thermal hypersensitivity and resting pain (Zahn et al., 2004).
2. In rat models of acute, local, inflammatory pain in which irritants are injected into the plantar tissue, the resulting hypersensitivity and electrophysiological changes are inhibited by blocking the action of NGF (Ma and Woolf, 1997).

Question 17

How can blocking NGF be achieved in a therapeutic agent?

Answer 17

Sequestering endogenous NGF with either anti-NGF antibodies or trkA– Immunoglobulin G (IgG) fusion proteins

Question 18

Composition of an alternative fusion protein other than trkA–IgG fusion proteins

Answer 18

heavy chains of IgG and peptides that bind to NGF (peptibodies)

Question 19

Which researchers demonstrated promise of fusion proteins in pain?

Answer 19

McMahon, 1995; Sutherland, 2004