Pain, Allostasis and Sensitization Brief overview of pain mechanisms

Pain Neuromatrix National Orthopedic Symposium 2019 Allostasis Neural Regulation Joshua Lee PT, MSc, MPT, PhD(c) Sensitization References Pain Neuromatrix |

Pain and Allostasis 1 Allostasis |

Allostasis – “Maintaining through change”

Process of adaptation to acute involving regulations in hormone levels and immune activation

Allostatic Load – “The price the body pays for being forced to adapt to adverse psychosocial or physical situations”

Overall, cumulative burden placed on the individual

Pain and Allostasis 2 Allostasis |

Pain and Allostasis 3 Allostatic Load | Anxiety, depression, stress, PTSD, cognitive fog/impairment - (Epinephrine, norepinephrine, , BDNF)

Chronic inflammation – joint effusion + systemic challenge (cortisol)

Heart/Lung condition (Systolic/diastolic BP, smoking, COPD, HTN, Arthritis, ILD, pulmonary HTN) Systemic conditions – Cholesterol (Serum HDL, total cholesterol, atherosclerosis), Diabetes (Glycosylated hemoglobin, blood sugar), Hormonal conditions (DHEA-S - HPA axis antagonist – dec. levels maladaptive, hysterectomy, endometriosis, prostate condition) y Gut microbiota (pain sensitivity, mood, systemic inflammation), abdominal girth (waist-to-hip ratio – inc. glucocorticoid activity, inc. adipose deposition), IBS, diet

Bone health / hormonal level – pain + deconditioning (Trauma, Menopause, BMD)

Tissue damage/small joint damage, Peripheral neuropathy, “smudging” effect (adverse posture/movement patterns, sensory ax – dermatomes/2pt discrim)

Pain and Allostasis 4 Neural Regulation |

Pain and Allostasis 5 Neural Regulation |

From Scholtz and Woolf, Nature Neuroscience (2002)

Pain and Allostasis 6 Neural Regulation |

Inflammatory “soup” (blue box) can cause sensitization – increased activity / responsiveness in nerves. Peripheral sensitization (PNS – limbs) and Central sensitization (CNS – brain and spinal cord)

From Scholtz and Woolf, Nature Neuroscience (2002)

Pain and Allostasis 7 Neural Regulation |

From Scholtz and Woolf, Nature Neuroscience (2002)

Pain and Allostasis 8 Sensitization |

Descending inhibitory Initial, sharp pain (A delta) control (PAG) Dull, burning pain Substance-P (C polymodal)

WDR Light touch (A beta)

GABA interneurons Glial cells

Allodynia +

= Immune and endocrine mediators (cytokines, norepinephrine, peptides)

Pain and Allostasis 9 Sensitization |

• Occurs in the PNS and CNS • Occurs in three broad ways • Activation-dependent (non-pathological) • “after-discharge” • Modulation of channels (non-pathologic) • I.e. Removal of Mg2+ block from NMDA channels (through activation of AMPA + Na influx) • Modification of receptors (pathologic) • Increased sensitivity to stimuli • Increased density of receptor channels • Increased release of

Pain and Allostasis 10 Sensitization | Association between nociception, learning, memory, and reward

Rational - Neo-cortex, pre-frontal cortex

Emotional - Anterior Cingulate, anterior insula, pre-frontal, hippocampus, parahippocampus Instinctual - Nucleus Accumbens, Thalamus, Amygdala, Periaqueductal Grey matter

Hyperactive – Primary somatosensory + motor (“smudging”), amygdala (fear), anterior insula (pain perception), thalamus (signal gain), parahippocampal gyrus (memory retrieval)

Hypoactive – ventromedial PFC/orbitofrontal cortex (cognitive processing, emotion and reward in decision making, executive function, functional attention), hippocampus (new memory encoding)

Pain and Allostasis 11 References |

• Melzack R. Pain and the neuromatrix in the brain. Journal of dental education. 2001 Dec 1;65(12):1378-82. • McEwen BS. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology. 2000 Feb 1;22(2):108-24. • Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain. 2011 Mar;152(3 Suppl):S49. • Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease?. The journal of pain. 2009 Nov 30;10(11):1113-20. • Tsao H, Galea MP, Hodges PW. Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain. Brain. 2008 Aug 1;131(8):2161- 71. • Janssen SA, Arntz A, Bouts S. Anxiety and pain: epinephrine-induced hyperalgesia and attentional influences. Pain. 1998 Jun 30;76(3):309-16. - Anxiety doesn’t necessarily influence pain, but attention does. Anxiety and distraction, showed different pain responses than anxiety and focusing on pain • Baron, Ralf. "Mechanisms of disease: neuropathic pain—a clinical perspective." Nature Reviews Neurology 2, no. 2 (2006): 95. • Kohno, Tatsuro, Haibin Wang, Fumimasa Amaya, Gary J. Brenner, Jen-Kun Cheng, Ru-Rong Ji, and Clifford J. Woolf. "Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity." Journal of Neuroscience 28, no. 17 (2008): 4533-4540.

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