Neurochemical Principles of Analgesia

The endocrine, immune and autonomic nervous systems respond to injury and pain through a chemical language of neurotransmitters, peptides, cytokines, and hormones.¹⁰¹Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p1).

Afferent channels of the peripheral nervous system continuously signal the state of body tissues to the brain.¹⁰²Jänig W, Levine JD. Autonomic-endocrine-immune interactions in acute and chronic pain. Wall and Melzack, Textbook of Pain, Chap 12, p206 (PDF p1). Feedback among these systems plays a prominent role in pain.¹⁰³Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p21).

Nociceptive signaling of injury creates an autonomic response, triggering the release of pro-inflammatory cytokines. This causes the endocrine system to respond by producing corticotropin-releasing hormone (CRH).¹⁰⁴Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p2,10).

Endogenous opioid analgesia

CRH acts synergistically with arginine vasopressin (AVP) to stimulate endogenous opioid peptide release. ¹⁰⁵O’Connor TM, O’Halloran DJ, Shanahan F. The stress response and the hypothalamic‐pituitary‐adrenal axis: from molecule to melancholia. Oxford Journal of Medicine, June 2000, Vol. 93:6, p323-333 (PDF p3)

Endogenous opioid peptides enhance analgesia and act with pituitary adrenocorticotrophic (ACTH) hormone to inhibit the stress response by inhibiting further hypothalamic CRH secretion. ¹⁰⁶O’Connor TM, O’Halloran DJ, Shanahan F. The stress response and the hypothalamic‐pituitary‐adrenal axis: from molecule to melancholia. Oxford Journal of Medicine, June 2000, Vol. 93:6, p323-333 (PDF p3)

Tissue trauma also enhances production of opioid peptides by immune system cells located in inflamed tissue.¹⁰⁷Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p15).

These endogenous opioids can be secreted into the surrounding tissue by specific releasing factors. This results in an activation of opioid receptors on sensory nerve endings and can elicit an inhibition of the generation and transmission of painful stimuli. The best described releasing factors so far are corticotropin-releasing factor (CRF) and IL-1.¹⁰⁸Schafer M. Cytokines and peripheral analgesia. Adv Exp Med Biol. 2003. p41

Feedback dysfunction

Feedback dysfunction among the stress systems can occur when a messenger chemical disappears, occurs in excess, or becomes confounded by exogenous products such as medications or substances of abuse.¹⁰⁹Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p21)

Feedback dysfunction is likely to contribute to chronic pain such as migraine headache, allodynia, idiopathic abdominal pain, non-cardiac chest pain, and a variety of multi-symptom syndromes.¹¹⁰Chapman C, Tuckett R, Song C. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain, 2008, Volume 9, Issue 2, Pages 122-145 (PDF p21).

Pain modulatory neurochemical systems

Pain modulatory neurochemical systems include endogenous opioids, autonomic (serotonergic, dopaminergic, and noradrenergic), inhibitory amino acids (cholecystokinin, galanin, and gamma amino butyric acid (GABA)).¹¹¹Kirkpatrick DR et al. Therapeutic Basis of Clinical Pain Modulation. CTS vol 8, issue 6, 11 May 2015, p849

Rostral ventromedial medulla (RVM) GABAergic neurons also facilitate mechanical pain by inhibiting dorsal horn enkephalinergic/GABAergic interneurons. These interneurons gate control pain through temporally coordinated enkephalin- and GABA-mediated presynaptic inhibition of somatosensory neurons. A descending disynaptic inhibitory circuit that facilitates mechanical pain is engaged during stress and could be targeted to establish higher pain thresholds.¹¹²Francois A et al. A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins. Neuron 93, 822–839, February 22, 2017, p 822.