Descending pain modulation and chronification of pain

Abstract

Purpose of review Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain ‘chronification’. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition. Recent findings Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual. Summary Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain ‘chronification’. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.

Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis

“…Using this model, we demonstrate that advanced OA pain is associated with central sensitization. Two aspects of central sensitization, spinal sensitization and descending facilitation, are observed in rats with persistent ongoing pain 29, 42 . These indicators of central sensitization were not observed in rats treated with a “low” dose of MIA, previously demonstrated as failing to induce ongoing pain in spite of development of joint pathology and signs of NSAID sensitive weight asymmetry and tactile hypersensitivity of the hindpaw 26 .…”

“…Another key component of central sensitization is descending pain facilitatory pathways from the rostral ventromedial medulla (RVM) 28 . Transient inactivation of the RVM by administration of lidocaine reverses evoked hypersensitivity and ongoing pain in animals with nerve-injury-induced pain, indicating that both evoked hypersensitivity and persistent ongoing or spontaneous pain are dependent on descending pain facilitatory pathways from the RVM 18, 29, 32, 40 . We therefore examined whether animals in this model of advanced OA pain develop central sensitization.…”

Subliminal (latent) processing of pain and its evolution to conscious awareness

“…Ongoing hyperalgesia may be a pre-determinant of more complex changes that lead to pain chronification (Woolf, 2011). Evidence for this includes that preoperative heat hyperalgesia predicts increased use of postoperative analgesics (Werner et al, 2010); potential alteration in descending modulatory systems (Miranda et al, 2015; Ossipov et al, 2014) are reported to be present in chronic pain patients (Jensen et al, 2012b; Yu et al, 2014); and intraoperative use of opioids may increase postoperative pain due to acute opioid tolerance or opioid induced hyperalgesia (Kim et al, 2014). Thus, from a number of perspectives, the addition of an opioid may produce changes in brain systems acutely (Upadhyay et al, 2012) or chronically (Upadhyay et al, 2010) that may then affect those being affected by the pain state .…”

“…Disruption of endogenous pain modulation (inhibition or facilitation (see (Bushnell et al, 2013) is also observed in human brain imaging studies across a number of diseases including fibromyalgia (Jensen et al, 2012b) migraine (Chen et al, 2017), orofacial pain (Mills et al, 2018), fibromyalgia (Harper et al, 2018), and diabetic neuropathy (Segerdahl et al, 2018) may be a nice working model for the concept presented here. While the model previously summarized for alterations in descending modulation and pain chronification has been review (Ossipov et al, 2014), the concept of an oscillatory state where the set point defines the presence or absence of pain. One basis for this may relate to changes in neurotransmitters such as serotonin or norepinephrine (Marks et al, 2009) or the inhibitory neurotransmitter GABA (Lau and Vaughan, 2014) in descending modulatory hubs such as the periaqueductal gray or the effects of such structures by more rostral brain areas (viz., anterior cingulate cortex (Eippert et al, 2009) may contribute to the inflection point seems credible.…”

Ağrının kronikleşmesine neden olan faktörler, patofizyoloji temelli tedaviler

“…[16] Ancak, pek çok kronik ağrılı durumlarda, inen yollardaki disregülasyon, yani ağrıyı durdurucu (antinosiseptif) mekanizmaların yeterli işlev görememesi ve ağrının fasilitasyonu [17] göz-lenmektedir. [18] Bu nedenle, kronik ağrılı hastalarda ağrılı uyaranlara artmış cevap -hipersensitivite (temporal sumasyon) ve eş zamanlı iki ağrılı uyarı verildiğinde ağrı inhibisyonunda (koşullu-ağrı modülasyo-nu) azalma gözlenir. [16] Kronik ağrılı [19][20][21][22][23] ve kronik bel ağrısı olan bireylerin beyin görüntüleme çalışma-larında yapısal değişiklikler de gözlenmiştir.…”