Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Ru-Rong Ji, Ph.D.; Andrea Nackley, Ph.D.; Yul Huh, B.S., M.S.; Niccolò Terrando, Ph.D.; William Maixner, D.D.S., Ph.D.


Anesthesiology. 2018;129(2):343-366. 

In This Article

Neuroinflammation in Chronic Overlapping Pain Conditions and Widespread Pain

Emerging evidence suggests that neuroinflammation contributes to the pathophysiology of coprevalent or coexisting chronic pain conditions that are referred to as chronic overlapping pain conditions, which include but are not limited to fibromyalgia, headache, temporomandibular disorder, back pain, irritable bowel syndrome, primary headaches, pelvic pain, and vestibulodynia. Chronic overlapping pain conditions are characterized by symptoms consistent with the dysregulation of sensory, inflammatory, and psychologic domains.[13,56,59,60] There is increased evidence that patients with chronic overlapping pain conditions exhibit increased basal and stress-induced levels of catecholamines (epinephrine and norepinephrine) in circulation[61–64] and reduced activity of catechol-O-methyltransferase,[65,66] a ubiquitously expressed enzyme that metabolizes catecholamines.[67] Chronic overlapping pain condition patients have functional variants in the COMT gene that result in reduced catechol-O-methyltransferase activity.[66,68–70] The "low catechol-O-methyltransferase activity" variants are associated with increased fibromyalgia[71–75] and temporomandibular disorder[76] onset and increased pain in response to experimental stimuli[76,77] and stressful events.[70,78,79] Consistent with clinical syndromes, in rodents sustained delivery of the catechol-O-methyltransferase inhibitor OR486 results in pain at multiple body sites that persists for weeks and altered pain- and anxiety-related volitional behaviors.[80,81–83] Persistent catechol-O-methyltransferase–dependent pain is initiated by peripheral β2- and β3-adrenergic receptors through release of nitric oxide, tumor necrosis factor-α, interleukin-1β, interleukin-6, and chemokine (CC motif) ligand 2 in plasma and maintained by increased tumor necrosis factor in central tissues.[80,83–84] Higher levels of nitric oxide derivatives (e.g., nitrite and nitrate) and proinflammatory cytokines have been found in patients with chronic musculoskeletal pain conditions.[13,85–89] Of note, patients with site-specific pain conditions (e.g., localized temporomandibular disorder or localized vestibulodynia) exhibit a balance in pro- and antiinflammatory cytokines, whereas those with chronic overlapping pain conditions fail to exhibit a compensatory increase in antiinflammatory cytokines.[13,60] Compared to patients with localized pain, those with chronic overlapping pain conditions also exhibit dysregulation in microRNAs (e.g., miR-let-7f) that augment immune response and proinflammatory cytokine production.[60] Together, these findings suggest that localized and anatomically widespread patterns of chronic pain are associated with distinct inflammatory profiles.

Widespread patterns of chronic pain exhibited by patients with chronic overlapping pain conditions may be attributed to previous injury or stressful events that produce long-lasting changes in nociceptor function, a phenomenon known as hyperalgesic priming. Preclinical studies have demonstrated that acute painful inflammation or nerve injury, as well as nonpainful stress, "primes" nociceptors so that they respond to a subsequent insult (e.g., prostaglandin E2 or epinephrine) for a prolonged duration due to activation of distinct kinase and gene transcription pathways.[4,90–93] In line with these findings, individuals with the "low activity" catechol-O-methyltransferase genotype report enhanced and prolonged pain after motor vehicle collisions or psychologic strain,[70,78,94] which are events that stimulate the sympathetic release of epinephrine known to sensitize nociceptors[95,96] and promote inflammation.[97–105] Thus, repeated environmental exposures to injury, inflammation, and stress in genetically predisposed individuals results in the transition from acute pain to chronic pain, in part through neuroinflammation (Figure 2). Of note, when a challenge of lipopolysaccharide is preceded by a surgical procedure, it has been shown that this early priming of spinal microglial cells increases the duration and intensity of pain through contributions to neuroinflammation.[106]