Suitability of Stimuli evoked Hypersensitivities in Hind paws as a Clinically Relevant Pain Behavioural Measure in Rat Model of Walker 256 Breast Cancer Cellinduced
Bone Pain: An Overview
Priyank A. Shenoy*
Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
- *Corresponding Author:
- Dr. Priyank A. Shenoy
Faculty of Pharmacy and Pharmaceutical
Sciences, Monash University, Melbourne
Tel: +61 3 9905 4000
E-mail: [email protected]
Received date: March 14, 2016; Accepted date: April 19, 2016; Published date: April 22, 2016
Citation: Shenoy PA (2018) Suitability of Stimuli evoked Hypersensitivities in Hind paws as a Clinically Relevant Pain Behavioural Measure in Rat Model of Walker 256 Breast Cancer Cell-induced Bone Pain: An Overview. Am J Pharmacol Pharmacother. Vol.5 No.1:4. doi:10.21767/2393-8862.100013
Metastases of breast cancer cells to the axial skeleton causes excruciating pain. The nature of pain hypersensitivities in metastasized bones is very complex due to the interplay of inflammatory, neuropathic and cancer-specific pain components. The existing drugs typically used to treat breast cancer-induced bone pain are inefficacious and often exhibit severe side effects. Hence, it remains to be an important goal of the ongoing research activities to seek novel analgesic compounds with better efficacy and tolerability. One of the key aspects in the process of understanding the mechanisms of pain progression and drug discovery to mitigate the hypersensitivities is employment of suitable preclinical animal models that mimic the complex human pathophysiology of breast cancer induced bone pain. Walker 256 breast cancer cell- induced bone pain model in rats is one such model that is known to show key resemblances to the clinical pain associated with bony metastases. The commonly used methods to assess pain hypersensitivities in Walker 256 cell- induced bone pain model in rats include stimuli evoked techniques like von Frey assessment and Randall-Selitto test. While other methods like assessment of gait parameters or spontaneous pain can also be used as beneficial complementary tools, this short review majorly sheds light on suitability of the stimuli evoked pain assessment methods in the hind paws of rats as being clinically relevant measures of assessing breast cancer induced bone pain in Walker 256 cell induced bony metastases.
Walker 256; Breast cancer-induced bone pain
Pain is a significant medical problem that co-exists with several
diseases including various types of cancer . Breast cancer cells
metastasize from the tissue of origin and establish themselves in
distant parts of the axial skeleton . The cancer cells growing
in the bone microenvironment cause osteolysis and sensitisation
of the peripheral nerve endings innervating the bones, thereby
causing excruciating pain . Breast cancer-induced bone pain
(BCIBP) causes severe morbidity because of the heterogeneous
combination of inflammatory, neuropathic and cancer-specific
components . The existing analgesic/adjuvant medications are
often insufficiently efficacious to combat this pain condition [5-8]. Thus it is very important to develop and characterize suitable
preclinical models of BCIBP so as to assist in drug discovery
programs aimed at identifying novel compounds having potential
to mitigate this often intractable pain condition. The rat model
of Walker 256 breast cancer cell induced bone pain is a highly
useful preclinical tool for assessment of mechanisms of BCIBP
and for seeking novel analgesics in the treatments thereof, as
it mimics key aspects of the human pathophysiology of this
Von Frey test using a series of filaments corresponding to different
levels of forces, and paw pressure test also called as Randall-
Selitto testing using increasing force delivered via a blunt cone shaped pusher, are two of the most common behavioural tests
employed in assessment of Walker 256 cell induced BCIBP in rats
. The plantar hind paw of rats, the anatomical region where von
Frey and Randall-Selitto stimuli are applied, is mainly innervated
by the tibial nerve and hence tibial bone pain sensations manifest
as hypersensitivities in the plantar aspect of the hind paws [12-15]. Hence, the traditional and most commonly used method to
measure tibial bone pain is assessment in the paws, with hundreds
of studies prevailing in the literature using this protocol. By using
intra-tibial injections of complete Freund’s adjuvant in the tibiae
of female Wistar rats, a study has elegantly established that the
bone pain induced by activation of tibial nerves directly manifests
as hind paw skin hypersensitivity . Cutaneous tests like the
von Frey testing and Randall-Selitto testing detect the current
levels of pain and have high clinical relevance as used in humans
A study involving the Department of Medicine of the University of
Florida (Gainesville, USA) has validated that mechanically evoked
pain is a highly relevant measure of the clinical pain intensity in
patients with deep pain of muco-skeletal origin . Similarly,
a study conducted in Edinburgh Cancer Centre (Edinburgh,
UK) also validated that assessing mechanical allodynia using
von Frey filaments is a direct measure of cancer induced bone pain in humans . Hence assessment of the stimuli evoked
hypersensitivities in the hind paws is physiologically relevant
assessment of bone pain. As per the previous studies published in
journals like PAIN [24-26], The Journal of Pain [27,28], European
Journal of Pain [29-31], Pain Medicine , Molecular Pain
[33,34], Nature Neuroscience  and others, it is a traditional
practice within the pain research fraternity to test the pain
hypersensitivities in the paw, following inoculation of cancer cells
in the tibia, without deploying other measures like gait or weight
bearing parameters. Along these lines, a recent report suggested
that a vast majority of around ~90% of the cancer induced bone
pain studies in the literature using MRMT-1 cells in rats used the
response evoked by the cutaneous stimuli applied to the foot as
a measure of bone pain . From the vast literature available on
Walker 256 cell induced bone pain model in rats, inoculation of
Walker 256 cell in the tibia always manifests as hypersensitivities
in the hind paws, without any discordance in paw-tibia correlation
being reported . The majority of studies in the literature that
used the Walker 256 breast cancer cell-induced bone pain model
in rats, used the hind paw as a location to test hypersensitivity
to evoked pain such as that induced by the von Frey test, rather
than spontaneous or movement evoked pain [18-45]. There are
many different studies very recently published, that used Walker
256 cells to induce bone pain in rats that only used stimuli evoked
behavioural measures such as von Frey paw withdrawal thresholds
in the hind paws, but not spontaneous movement evoked or
weight bearing measures to assess pain hypersensitivities [35-60]. The vast experience of different laboratories conducting preclinical
cancer-pain research around the world with the Walker
256 cell induced BCIBP model in rats strongly emphasizes on
the suitability of stimuli evoked hypersensitivities in paws as the
correct measure of bone pain in this particular model.
However, it is noteworthy that dissociation is observed in
between skeletal pain behaviors and skin hypersensitivity in a
male C3H mouse model of intra-femoral injection of NCTC 2472
osteosarcoma cells . It is known that different types of cell
lines or tumors exhibit distinct pain behavioral patterns . It is
the unique interaction between each of the cancers colonising the
bone and the nerve innervation that predominantly decides the
nature of pain manifestation . On these grounds, a previous
study highlighted the fact that neither spontaneous pain nor
ambulatory pain is the best measure of cancer induced bone pain
for all models triggered by different cancer cell lines in general
. It showed that intra-osseous injection of B16-F10 melanoma
cell line in the femur did not produce either the spontaneous pain
or the ambulatory pain. The bone pain induced by B16-F10 cell
line manifested only as hind paw skin hypersensitivity. Similarly,
C26 colon cancer cell line did not produce spontaneous pain
behavior. Hence, the spontaneous or ambulatory pain are not
the universal measures of bone pain at least in some models
like B16 cell model and C26 cell model. In alignment to this preclinical
animal based study, a clinical study of cancer induced
bone pain also reported that in patients with breakthrough
pain, which is commonly triggered by a stimulus , patients
were not more likely to experience pain at the weight-bearing
bone sites, compared to patients without pain . Additionally,
allodynia and gait behaviours are two independent phenomena.
Neuropathic pain is one of the key components of cancer induced
bone pain , and allodynia (measured by tests like von Frey) is a
more reliable measure of the neuropathic pain component, rather
than gait behaviours (weight bearing or spontaneous pain during
ambulation) . The changes in gait parameters can typically be
due to the tendency of animals to avoid allodynia produced by
contact of the paw with the floor . The gait changes might
not necessarily relate well to pain hypersensitivities [66-72].
There are several evidences that suggest that changes in gait
parameters like guarding the hind paw during ambulation or
changes in weight bearing are significantly driven by the adaptive
changes and psychological influences (pain-avoidance and fear
due to cognition), rather than the current levels of pain intensity
[66-82]. Whereas, both the von Frey and Randall-Selitto tests
that are also used in humans to assess pain hypersensitivities,
detect the current levels of pain and have high clinical relevance
[16-21]. This is probably one of the most important reasons
why large number of published studies used stimuli-evoked
methods like the von Frey and Randall-Selitto tests to assess pain
hypersensitivities in the hind paws of animals following unilateral
tibial inoculation of cancer cells.
The vast literature on Walker 256 cell induced BCIBP model in
rats strongly suggests that stimuli evoked pain behaviours in the
hind paws of rats is an appropriate measure of cancer induced
bone pain in this particular model. However, a complementary
assessment of measures like ambulatory pain, spontaneous pain
or pain evoked by weight bearing on the hind paws of rats might
add more value to the studies in future as these tests might be
considered relatable to pain assessments in humans.
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