Biology Reference
In-Depth Information
reduced the emetic threshold of the D2 agonist, apomorphine (Carpenter et al.
1988
). One consequence of elevated levels of cAMP is the transcriptional activation
of the early response gene
c-fos
, following upstream activation of the transcription
factor, cAMP response element binding (CREB) by protein kinase A. This method
was employed to demonstrate increased c-fos immunoreactivity in neurons within
area postrema and nucleus tractus solitarius following systemic administration of a
PDE4 inhibitor and providing conclusive proof that this drug class can lead to the
activation of neurons within the emetic centers of the central nervous system (CNS)
(Bureau et al.
2006
). Direct application of a highly potent PDE4 inhibitor via
intracerebroventricular administration in order to limit systemic bioavailability
provide a means of directly activating neurons within the CNS, consequently
resulting in emesis in the ferret (Robichaud et al.
1999
). This ability of PDE4
inhibitors to induce emesis in the ferret was inhibited by the alpha2-selective
agonist, clonidine (Robichaud et al.
2001
) and suggested that raising cAMP within
central noradrenergic terminals by PDE4 inhibitors promoted emesis, and this could
be attenuated via alpha
2
-adrenoceptor mediated inhibition of adenylyl cyclase.
The emetic response to systemically administered PDE4 inhibitors is reduced by
anti-emetic agents including the 5HT3-antagonist, ondansetron, and the NK1 antag-
onist, (+)-(2
S
,3
S
)-3-(2-[
11
C]Methoxybenzylamino)-2-phenylpiperidine (CP-99,994)
(Robichaud et al.
1999
,
2001
). Similarly, the increased expression of c-fos
within the emetic centers of the brain was also reduced following treatment
with the NK
1
antagonist, RP67580, thus implicating substance P in this response
(Bureau et al.
2006
).
Many studies have documented the expression of PDE4D within the area post-
rema, nucleus tractus solitaris, and nodose ganglion neurons in various species
including man and implicated this isoform in nausea and vomiting (Cherry and
Davis
1999
; Takahashi et al.
1999
; Perez-Torres et al.
2000
; Lamontagne et al.
2001
). However, it should also be recognized that detectable transcripts for PDE4B
were also found within the nucleus tractus solitaris and area postrema in humans
and rodents, respectively, and could just as well be involved in the emetic response
(Perez-Torres et al.
2000
). Consequently, there is a general consensus that inhibi-
tion of PDE4D is responsible for side effects such as nausea and emesis. Since
rodents lack an emetic reflex, it is not possible to directly investigate the role of
different isoforms of PDE4 in emesis in this model. However, a surrogate biological
response, which measures the reversal of anesthesia induced by alpha
2
-adrenoceptor
agonists (e.g., clonidine, xylazine), has been used to study the role of PDE4
subtypes in emesis (Robichaud et al.
2001
,
2002a
). Deletion of PDE4D and not
PDE4B reduced the duration of anesthesia induced by xylazine, compared with
wild-type mice, and the ability of PDE4 inhibitors to shorten xylazine-induced
anesthesia was impaired in PDE4D but not PDE4B knockout mice (Robichaud et al.
2002b
). Together these studies suggested that PDE4 inhibitors with low affinity for
PDE4D should have reduced emetic potential.
However, the validity of this hypothesis has been questioned in light of the deve-
lopment of PDE4 selective inhibitors which preferentially distribute to the brain and
are relatively free from emesis in a range of animal models (Burgin et al.
2010
).
