Pain Research Forum: Papers: 21 Jun 2014 – 27 Jun 2014

Pain Research Forum: Papers: 21 Jun 2014 – 27 Jun 2014

The Papers of the Week is now sponsored by the American Pain Society.   Funding from the APS is being used to support this popular feature for 2014.

The Pain Research Forum’s Editors “comb through the latest PubMed postings to bring you the most up-to-date and relevant papers in the field of pain research“.

Editors’ Picks

Classic Papers

Archive

Here is a sampling of this week’s papers:

Epigenetic regulation of persistent pain. [Transl Res. 2014] – PubMed – NCBI

Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues.

Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development/maintenance of persistent pain and possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain.


Emerging targets in neuroinflammation-driven pain [Nat Rev Drug Discov. 2014] – PubMed – NCBI

Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression.

Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain.

This Review focuses on emerging targets – such as chemokines, proteases and the WNT pathway – that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders.


The Journal of Headache and Pain | Abstract | The serotonin transporter gene polymorphism is associated with the susceptibility and the pain severity in Idiopathic Trigeminal Neuralgia patients

Background:  To investigate the possible association between the serotonin transporter gene (5-HTTLPR)  and rs 25531 polymorphism and the susceptibility and the pain severity in Trigeminal  Neuralgia patients.

Methods: A total of 244 TN patients and 280 age and sex matched healthy volunteer were recruited.  5-HTTLPR and rs 25531 genotyping were performed. All patients received the carbamazepine  treatment and the treatment response was evaluated at 6 months.

Results: The genotype distribution of 5-HTTLPR between TN patients and controls were significantly  different.

Conclusion: The 5-HTTLPR polymorphism is associated with the susceptibility to TN and pain severity  of TN.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production


The risk of suicide mortality in chronic pain patients [Curr Pain Headache Rep. 2014] – PubMed – NCBI

Chronic pain has long been considered an important risk factor for suicidal behavior. Less well understood are the factors associated with the increased risk for suicide death within chronic pain populations.

The purpose of this review is to examine recent research with regard to rates of and risk factors for suicide mortality in patients with chronic musculoskeletal pain.

We conclude that patients with a number of chronic pain states are at increased risk for suicide death, and that this risk appears to be due, at least in part, to other well-known correlates of pain such as depression and substance use disorders. However, in all likelihood, there are aspects of chronic pain itself that add uniquely to an individual’s suicide risk profile. Lastly, we address a theoretical perspective and offer recommendations for clinical practice.


Biased agonism of the mu opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind placebo-controlled crossover study in healthy volunteers. [Pain. 2014] – PubMed – NCBI

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating mu-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects

Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 seconds latency versus 75 seconds for morphine, p<0.02), with faster onset and similar duration of action.

Thus in this study TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy


Molecular Pain | Abstract | Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia

Background:
Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors  contribute to the transition from acute to chronic pain is largely unknown.

Conclusion:
ASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle  nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity  are essential for the development of long-lasting hyperalgesia in acid-induced, chronic,  widespread muscle pain.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production


TRPs and Pain. [Handb Exp Pharmacol. 2014] – PubMed – NCBI

Pain usually occurs as a result of tissue damage and has a role in healing and protection. However, in certain conditions it has no functional purpose and can become chronic and debilitating. A demand for more effective treatments to deal with this highly prevalent problem requires a better understanding of the underlying mechanisms.

TRP channels are associated with numerous sensory functions across a wide range of species. Investigation into the expression patterns, electrophysiological properties and the effects of channel deletion in transgenic animal models have produced a great deal of evidence linking these channels to transduction of noxious stimuli as well as signalling within the pain system.


Glycine transport inhibitors for the treatment of pain [Trends Pharmacol Sci. 2014] – PubMed – NCBI

Opioids, local anesthetics, anticonvulsant drugs, antidepressants, and non-steroidal anti-inflammatory drugs (NSAIDs) are used to provide pain relief but they do not provide adequate pain relief in a large proportion of chronic pain patients and are often associated with unacceptable side effects.

Inhibitory glycinergic neurotransmission is impaired in chronic pain states, and this provides a novel target for drug development. Inhibitors of the glycine transporter 2 (GlyT2) enhance inhibitory neurotransmission and show particular promise for the treatment of neuropathic pain. N-arachidonyl-glycine (NAGly) is an endogenous lipid that inhibits glycine transport by GlyT2 and also shows potential as an analgesic, which may be further exploited in drug development.

In this review we discuss the role of glycine neurotransmission in chronic pain and future prospects for the use of glycine transport inhibitors in the treatment of pain.


Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord [Front Neural Circuits. 2014] – PubMed – NCBI

Dopamine (DA) modulates spinal reflexes, including nociceptive reflexes, in part via the D3 receptor subtype. We have previously shown that mice lacking the functional D3 receptor (D3KO) exhibit decreased paw withdrawal latencies from painful thermal stimuli. Altering the DA system in the CNS, including D1 and D3 receptor systems, reduces the ability of opioids to provide analgesia.

Our data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state.

We propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway.

 

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