MD Biosciences Blog

Inflammatory Mediators & Neuropathic Pain Models

Posted by MD Biosciences on Jan 24, 2011 5:40:00 AM

Neuropathic pain is a chronic pain condition caused by lesion or inflammation affecting the nervous system. It is relatively common, can be severely debilitating and clinically significant relief is often difficult to achieve in part because conventional opioid therapy is typically less effective for neuropathic pain. The common symptoms of neuropathic pain include allodynia (pain resulting from normally innocuous stimulus), hyperalgesia (increased sensitivity to painful stimuli) and spontaneous pain. It has been widely known that a number of mechanisms are involved such as ectopic excitability of sensory neurons, altered gene expression of sensory neurons, and sensitization of neurons in the dorsal horn of the spinal cord. However, increasing evidence and research points to the interaction between the immune system and the nervous system playing a crucial role in the the underlying mechanisms of neuropathic pain (1). Following nerve damage, an inflammatory response is initiated: complement system is activated, a variety of inflammatory cells are recruited to the site of nerve injury, dorsal root ganglia (DRG) and to the spinal dorsal horn. Activation of immune-like glial cells   and an upregulation of inflammatory mediators all contribute to neuropathic pain (1-10).

Read More

Topics: Pain, Inflammation

Pain & Inflammation Link | Need For Relevant Preclinical Models

Posted by MD Biosciences on Sep 15, 2010 2:12:00 PM

Considering the close link between inflammation and the pain process, preclinical efficacy models that allow the evaluation of both pain and inflammation are crucial to developing new therapies.

One of the prominent features of inflammatory conditions is that normally innocuous stimuli produce pain. The pain process involves several areas which include nociception, pain perception and pain behavior. After tissue injury or nerve damage, neurons along the nociceptive pathway may display enhanced sensitivity and responsiveness. A variety of events and agents can contribute to this sensitization, including the release of inflammatory mediators (such as cytokines or prostaglandins) or the release of algesic substances from damaged cells. Cytokines and prostaglandins are important mediators of inflammation that also have an effect on pain and nociceptors. Cytokines have influence over sensory neurons and may act directly upon nociceptors or indirectly by stimulating the release of prostaglandins, which are considered sensitizing agents and in some cases directly activate nociceptors.

What would efficacy and mechanistic models that allow you to evauate the effects on pain as well as the contributing inflammatory conditions mean for your therapy?

Read More

Topics: Pain, Inflammation

Why Post-operative Pain Is Under-Treated

Posted by MD Biosciences on Mar 23, 2010 9:22:00 AM

Adequate pain relief following surgical procedures is well-documented to improve the degree and time course of patient recovery. Nontheless, post-operative pain remains grossly under treated, with up to 70% of patients reporting moderate to severe pain following surgery (1). Perhaps the biggest underlying contributor to the under treatment of post-operative pain is simply a lack of information, both on the part of basic scientists as well as clinicians. Scientists are in the relatively early stages of investigation into the specific mechanisms contributing to the development of incisional pain, which may differ from those mediating acute pain induced by chemical or inflammatory algesic agents. Currently, clinicians essentially rely on treatments that have been developed for other painful conditions, most notably opioids, the side effects of which can hinder rehabilitation and recovery. 

Read More

Topics: Pain

Pain Processing: Cation Channel Blockers. Choosing Pain Models

Posted by MD Biosciences on Jan 11, 2010 11:54:00 AM

Sodium and calcium cation channel blockers.

Read More

Topics: Pain

Cannabinoid System | A Target For Pain Relief.

Posted by MD Biosciences on Nov 17, 2009 2:00:00 PM

The body's cannabinoid system consists of two cannabinoid receptors, CB1 and CB2, their endogenous ligands, which include 2-arachidonoyl glycerol (2-AG) and anandamide (AEA), and the enzymes that regulate the synthesis and degradation of these ligands. While the endogenous cannabinoid system serves naturally to modulate pain transmission, it can be exploited to provide more robust relief, either through administration of agonists at CB1 or CB2 receptors or through inhibition of degrading enzymes to increase endogenous cannabinoid levels.

CB1 receptors are expressed in neurons throughout the central and peripheral nervous system, including in the DRG, where noiciceptor cell bodies reside, the dorsal horn of the spinal cord, and the PAG, all of which are important sites for modulation of pain transmission. CB2 receptors, on the other hand, are not found in the CNS under normal conditions (although they may be upregulated in nociceptive neurons after injury) and are instead expressed in a variety immune cells and microglia. Although activation of either receptor can promote pain relief, CB1 receptors are responsible for the centrally-mediated psychomimetic side effects that sometimes accompany administration of cannabinoid receptor agonists such as tetrahydrocannabinol (THC).

Both CB1 and CB2 are GPCRs that signal predominantly through Gi/o to decrease VGCC conductance and activate GIRKs to hyperpolarize cells. Therefore, ligand binding to cannabinoid receptors results in decreased release of excitatory neurotransmitters from nociceptive neurons and post-synaptic cells exhibiting decreased excitability for signals they do receive. Activation of cannabinoid receptors on immune cells can similarly inhibit their function and thereby indirectly modulate pain processing. Since CB2 receptors are found primarily on immune cells and microglia, this indirect, anti-inflammatory effect is the primary mechanism by which CB2-selective agonists modulate pain responses.

Cannabinoid agonists have shown efficacy in acute models such as tail flick and capsaicin injection, as well as carrageenan and CFA inflammatory pain models. Translation from animal models to the human condition has been documented for a variety of neuropathic conditions as well as for post-operative pain relief; therefore, both neuropathic and post-operative pain models would be appropriate for testing novel compounds designed to target the cannabinoid system as well.
Read More

Topics: Pain

α2-adrenergic Agonists & Tricyclic Antidepressants | Pain Model

Posted by MD Biosciences on Oct 14, 2009 2:14:00 PM

α2-adrenergic receptors (α2ARs) are found in many areas in throughout the nervous system, but the α2ARs on pre- and post-synaptic neurons in the dorsal horn of the spinal cord are the main target for both endogenous and exogenous analgesia. One of the major descending inhibitory pain pathways involves the projection of noradrenergic neurons in the locus ceruleus back down to the spinal cord to activate α2ARs at this site. These receptors can also be targeted pharmacologically through administration of selective agonists or through the inhibition of noradrenaline (also known as norepinephrine) reuptake by drugs such as tricyclic antidepressants.

Read More

Topics: Pain