Preclinical Drug Discovery Blog

The management of post-operative pain is a challenge for both physicians and patients. In addition to a comfortable recovery, the prevention of chronic pain and improvement of conventional outcomes are important in post-operative pain management.

Preclinical stroke models are critical to our understanding of the mechanisms and neurological deficits following human stroke. While reducing infarct size is a focus of stroke therapies, much attention is also on neuroprotective properties. Adding behavioral and functional outcome measures to preclinical studies is important to evaluate the impact on impairments that occur following stroke: learning, memory, motor function and sensory. There are many behavior tests, each having different sensitivities to deficits associated with particular areas of brain damage.

Management of acute pain related to surgical intervention, termed postoperative pain, continues to be a major problem facing physicians and patients today. The most common method for addressing post-operative pain is through pharmacotherapy. [1,2] Table 1 lists a selection of the most common analgesics used to treat acute surgical pain, their methods of delivery, and the mechanism by which they are thought to act. [1] Significant progress in the pain management field has been made in recent years mostly in the areas of new delivery methods and multimodal analgesia. Novel drug delivery systems for postoperative pain medications include, for example, patient-controlled analgesia, means of sustained or extended release, transdermal delivery using iontophoresis, and transmucosal and intranasal delivery systems. While a few of these methods may not yet be approved in all geographies, the majority now serve as new tools available to physicians to treat their surgical patients. [1,2] Multimodal analgesia is based on the idea that simultaneous administration of more than one pain therapy strategy offers opportunities for results that are either additive or synergistic. Although clinical data on these types of strategies are still somewhat inconsistent, some clinical trial data do demonstrate improved outcomes and reduced incidence of persistent post-operative pain. [1]

In the context of neuropathic pain (NP), toll-like receptor member 4 (TLR4) is known to be expressed exclusively on spinal microglia and significantly up-regulated upon peripheral nerve injury. TLR4-knockout mice display reduced effects of chronic chonstriction injury (CCI) induced nerve damage. Similary, TLR4 loss-of-function mutant mice as well as TLR4 antisense oligonucleotide-treated rats both display attenuated neuropathic pain symptoms after nerve damage. Further, intrathecal administration of a TLR4 antagonist after CCI treatment results in relief of neuropathic pain symptoms. Many exogenous and endogenous ligands are known to stimulate TLR4-mediated signaling. However, both in vitro and in vivo studies involving spinal nerve ligation (SNL) treated animals implicate Fibronectin in neuropathic pain-related TLR4 signaling. Fibronectin is an extracellular matrix protein that is commonly produced in response to tissue injury. When administered intrathecally to intact rats, Fibronectin induces microglial up-regulation of the purigenic receptor, P2X4, and symptoms of neuropathic pain. This stimulation of P2X4 expression can be suppressed by interuption of Fibronectin binding the TLR4 receptor after SNL injury in rats. 

Osteoarthritis (OA) is a widespread condition that affects greater than 70% of the elderly population and poses a heavy cost burden on healthcare. It is a chronic degenerative disease characterized byt the loss of articular cartilage components, which affects the entire joint structure. One of the major complaints by OA patients is the loss of joint function as well as chronic pain. Current therapies are focused on alleviating joint pain, however full pain relief is rarely experienced and significant side affects are commonly present. Research is not only focused disease pathology but also on understanding the mechanisms responsible for induction and maintenance of pain states.

There are currently a large number of well-characterized, ischemic stroke animal models available for pre-clinical research. These models can be categorized into those two groups – those for the study of stroke-associated risk factors and those for the study of stroke pathophysiology. The latter can be further separated into models of focal verses global ischemia and are listed:[1]

The most common form of stroke is acute ischemic stroke (approximately 85% of cases), which is caused by either an atherothrombosis in a major cervical or intracranial artery or an embolism that travels from the heart. The resulting occlusion causes a sudden deficiency of oxygen and glucose in the brain region normally serviced by the blocked artery. Victims of large-vessel ischemic strokes lose on the order of 100 million neurons per hour prior to treatment, causing immediate, permanent neural damage in the infarct area, termed the ischemic core. Further neural damage occurs in the areas surrounding the core, called the penumbra, where the tissue becomes highly inflamed and slowly dies. Stroke sufferers experience a range of neurological deficits including partial paralysis, impaired memory, loss of speech, and/or decreased cognition and many become permanently disabled, requiring institutional care. [1-4]

Neuroinflammation is a common thread in neuropathic pain (NP), regardless of the conditions under which neuropathic pain develops. This opens up a whole new avenue for investigations into neuropathic pain pathology. Since the primary cell type responsible for immune-like functions in the CNS is microglia, many researchers have turned their attention toward working to better understand microglial physiology and its potential involvement in neuropathic pain.

Of the roughly 70% of cells in the central nervous system (CNS) that are glia, appromixately 5-10% are microglial cells. Microglial cells are derived from peripheral myeloid progenitor cells that enter the CNS during embryonic development. Though ubiquitous in the CNS, microglial cell densities vary by region. They function to provide structural and trophic support to neurons and serve as the resident immune-competent cells of the CNS, tasked with:

We get a lot of questions on the various neuropathic pain models and how to choose the one that's most appropriate or a comparison of what's involved with each model (e.g. surgery, behaviors, centralization, peripheral vs central involvement etc). We thought it may be helpful to discuss the various aspects of these models to assist with the selection and understanding of the mechanisms and behaviors. Of course, it ultimately depends on the drug target and the pathway involved and we can certainly discuss individual specifics with you.