Title:Pain-Related Behavior and Brain Activation in a Cynomolgus Macaque Model of Postoperative Pain
Volume: 17
Issue: 5
Author(s): Aldric Hama*, Takahiro Natsume, Shin`ya Ogawa, Yuji Awaga, Ikuo Hayashi, Akihisa Matsuda and Hiroyuki Takamatsu
Affiliation:
- Pharmacology, Hamamatsu Pharma Research, Inc., 1-3-7, Shinmiyakoda, Kita-ku, Hamamatsu, Shizuoka, 431-2103,Japan
Keywords:
Pressure hyperalgesia, functional magnetic resonance imaging, primary hyperalgesia, translational preclinical
model, insula, cingulate.
Abstract: Background: Inadequate postoperative pain management could lead to persistent pain and
this is, in part, due to incomplete understanding of the mechanism of postoperative pain. Currently
available rodent models may have limited translatability to clinical postoperative pain. Thus, a preclinical
model of postoperative pain was developed in the cynomolgus macaque, a species that is
phylogenetically closer to humans than rodents.
Method: The presence of pressure hypersensitivity was assessed with non-noxious pressure applied
proximally and distally (approximately 10 cm) to an abdominal incision in macaques. The effect of the
opioid morphine (intramuscular, i.m.), the nonsteroidal anti-inflammatory drug diclofenac (i.m.) and
the anticonvulsant pregabalin (i.m.) on pressure hypersensitivity was evaluated one and two days following
surgery. Brain activation during non-noxious pressure stimulation was observed with functional
magnetic resonance imaging.
Results: Hypersensitivity to non-noxious pressure applied proximally and distally (approximately 10
cm) to the incision was observed, lasting for up to seven days and three days, respectively, following
surgery. Postoperative pressure hypersensitivity was attenuated with morphine but not with either diclofenac
or pregabalin. Bilateral activation of the insular cortex and cingulate cortex was observed
during non-noxious pressure stimulation proximal to the incision, which was attenuated with morphine.
By contrast, pregabalin reduced only cingulate cortex activation.
Conclusion: The lack of antinociceptive efficacy of pregabalin on postoperative pain could be due to
the incomplete suppression of pressure-evoked brain activation. It is speculated that incomplete postoperative
pain relief observed in general could be due to residual or persistent activity of key pain nuclei
such as the insular cortex. The current macaque model could be used for further elaborating the
mechanism of postoperative pain as well as confirming the efficacy of potential treatments for the
management of postoperative pain.
