KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

The neuropathic phenotype of the K/BxN transgenic mouse with spontaneous arthritis: pain, nerve sprouting and joint remodeling

The adult K/BxN transgenic mouse develops spontaneous autoimmune arthritis with joint remodeling and profound bone loss. We report that both males and females display a severe sustained tactile allodynia which is reduced by gabapentin but not the potent cyclooxygenase inhibitor ketorolac. In dorsal horn, males and females show increased GFAP+ astrocytic cells; however, only males demonstrate an increase in Iba1+ microglia. In dorsal root ganglia (DRG), there is an increase in CGRP+, TH+, and Iba1+ (macrophage) labeling, but no increase in ATF3+ cells. At the ankle there is increased CGRP+, TH+, and GAP-43+ fiber synovial innervation. Thus, based on the changes in dorsal horn, DRG and peripheral innervation, we suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, an assertion consistent with the analgesic pharmacology seen in this animal. These results indicate the relevance of this model to our understanding of the nociceptive processing which underlies the chronic pain state that evolves secondary to persistent joint inflammation.

Study of humoral immunity indicators for evaluation of chronic pain state

189 patients with chronic low back pain (LBP) caused by vertebral pain syndrome were surveyed. Pain levels, measured by differential visual-analog scale, and variations of natural antibody levels to the pain bioregulators (nAbs) in blood serum at LBP were studied during 21 days. We revealed gender features of immuno-profiles: more elevated nAbs levels against opioids at women at 1st day and equal levels in both gender groups at 21 days. Generally nAbs levels remained above normal up to 21st day in most of patients despite a three-fold decrease of pain intensity. A significant decrease in nAb levels was found in 4-20% of patients, depending on the bioregulator. These observations support the hypothesis that antibodies can be a factor in the prolongation of pain, so the analysis of the dynamics of nAbs for patients with LBP can be recommended, which will be useful to predict the further course of the disease.

Preventive Analgesia for the Management of General Surgical Pain

Pain created by surgery has the ability to produce both structural and functional changes in pain pathways. These changes may be reduced if timely and adequate pain relief is delivered to the patient. Poor control of pain can result in remodeling of the “hardwired” pathways involved in pain transmission, which can result in central sensitization and hyperalgesia. Furthermore, poorly controlled pain and delay in its recognition may lead to a chronic pain state, further complicating the patient’s recovery and quality of life. A multimodal approach taking into account psychosocial aspects of the patient is more likely to mitigate the development of chronic postsurgical pain (CPSP).

Pathophysiology of Pain: Why Does Chronic Pain Hurt? The Multiple Hit Theory

Acute pain hurts and most often is the result of tissue injury. Chronic pain also hurts. Although those who suffer from chronic pain also tend to associate the onset with an injury, illness, or surgical procedure; the root cause is far more complex. Chronic pain most often does not follow dermatomal distributions associated with any injury, disease or surgical procedure. And more often than not, chronic pain sufferers also suffer from various forms of depression and/or anxiety. The process of central sensitization resulting from tissue injury has been elucidated, as has many of the molecular changes within the brain that perpetuate chronic pain. Genetics, epigenetics, environmental stressors, and emotional stressors all play roles to varying degrees in the development of the chronic pain state. This article explores how synaptic memories form in the brain as a result of both physical and emotional traumas (multiple hits) resulting in progression to chronic pain, because of failure of the brain’s descending modulatory mechanisms to prevent or control “the pain.” This review contains 15 figures, and 178 references. Key words: Epigenetics, memory, central sensitization, chronic pain

The Use of Drug Testing in Promoting Treatment Adherence in Pain Medicine

Drug testing has become an important component of a comprehensive risk assessment and mitigation program when prescribing controlled substances to patients with chronic pain. State and federal opioid prescribing guidelines strongly recommend the use of drug testing, although there is lack of evidence in the literature supporting the efficacy of drug testing in reducing prescription opioid abuse. Drug testing can be useful in facilitating adherence to prescribed medications. This chapter provides an overview of the strengths and weaknesses of drug testing in pain medicine, insights into laboratory and test selection, test interpretation, and communicating results to patients within a patient-centered model.