The Opioid Epidemic
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
Tonic activation of descending bulbospinal (medulla to spinal cord) pain facilitatory loops from the rostral ventromedial medulla (RVM) to the spinal cord play a role in opioid-induced hyperalgesia. Opioid exposure in the RVM can lead to an increased descending facilitation of pain.16 Upregulation of spinal dynorphin has been implicated.1 An increase in dynorphin enhances primary afferent neurotransmitter release.1 Dynorphin has also been shown to potentiate NMDA receptors.17 Upregulated spinal dynorphin is pronociceptive and is required for the maintenance of persistent neuropathic pain.18 Lesioning the dorsolateral funiculus prevents the increase of dynorphin and the presence of the excitatory neuropeptide calcitonin gene-related protein (CGRP).19 In the same vein, treatment with a selective k-opioid receptor antagonist also reduced established opioid-induced hyperalgesia.20
Opioid Therapy for Chronic Noncancer Pain: Cautions, Concerns, Misconceptions, and Potential Myths
Mark V. Boswell, B. Eliot Cole in Weiner's Pain Management, 2005
The development of hyperalgesia has been hypothesized to be a form of neurotoxicity associated with the accumulation of opioid metabolites (Pereira, 1997), variations in opioid receptor concentrations (Wilson, 2001), or activation of descending rostral ventromedial medulla mechanisms that facilitate pain (Ossipov et al., 2003). While the exact mechanism responsible for this opioid effect remains unknown and is no doubt complex, its existence is problematic from a pain treatment perspective and poses a paradox to practitioners. That is, attempts to relieve pain via opioid administration may, for some individuals, actually provoke increased pain, as may opioid cessation following even very brief opioid exposure.
Physiology of pain
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2015
Descending pathways arising from the periaqueductal grey in the midbrain and the rostral ventromedial medulla (RVM) project to the dorsal horn and inhibit pain transmission. The periaqueductal grey and RVM contain high concentrations of opioid receptors and endogenous opioids. The neurotransmitters of the descending pathways are noradrenaline and serotonin (monoamines).
Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?
Published in Current Medical Research and Opinion, 2020
Filippo Caraci, Flaminia Coluzzi, Franco Marinangeli, Sebastiano Mercadante, Giuseppe Rinonapoli, Patrizia Romualdi, Mariaflavia Nicora, Anthony H. Dickenson
Supraspinal involvement is central to the experiential aspects as well as in the affective components of pain. Multiple regions are involved, such as the hypothalamus, amygdala and cortex, as well as the nucleus accumbens and the periaqueductal grey5,8. Pathways run back from the brain to the spinal cord and many of the descending tracts are monoaminergic: at spinal synapses, the descending pathways induce the release of several mediators, including endogenous opioids, NA, serotonin (5-HT) and gamma-aminobutyric acid (GABA), thus modulating the transmission between primary and secondary neurons9. Remarkably, NA pathways exert an inhibitory effect on the transmission of acute and chronic pain, thus counteracting the establishment of chronic pain9. Conversely, serotoninergic pathways may have a facilitatory effect in the advanced stages of chronicity and therefore, might play a pro-nociceptive role10. The imbalance between amplified spinal ascending signals and inadequate activation of the descending inhibitory pathways plays a key role in the development and maintenance of many chronic pain syndromes9. Activity in the descending noradrenergic system can be gauged in animals and humans by diffuse noxious inhibitory controls (DNIC) and conditioned pain modulation (CPM), respectively, whereby one painful stimulus can inhibit another11. This control mechanism often fails in persistent pain states, allowing descending facilitation from the rostral ventromedial medulla (RVM) to dominate.
Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?
Published in Current Medical Research and Opinion, 2020
Filippo Caraci, Flaminia Coluzzi, Franco Marinangeli, Sebastiano Mercadante, Giuseppe Rinonapoli, Patrizia Romualdi, Mariaflavia Nicora, Anthony H. Dickenson
Supraspinal involvement is central to the experiential aspects as well as in the affective components of pain. Multiple regions are involved, such as the hypothalamus, amygdala, and cortex, as well as the nucleus accumbens and the periaqueductal grey5,8. Pathways run back from the brain to the spinal cord and many of the descending tracts are monoaminergic: at spinal synapses, the descending pathways induce the release of several mediators, including endogenous opioids, NA, serotonin (5-HT) and gamma-aminobutyric acid (GABA), thus modulating the transmission between primary and secondary neurons9. Remarkably, NA pathways exert an inhibitory effect on the transmission of acute and chronic pain, thus counteracting the establishment of chronic pain9. Conversely, serotoninergic pathways may have a facilitatory effect in the advanced stages of chronicity and therefore, might play a pro-nociceptive role10. Imbalance between amplified spinal ascending signals and inadequate activation of the descending inhibitory pathways plays a key role in the development and maintenance of many chronic pain syndromes9. Activity in the descending noradrenergic system can be gauged in animals and humans by diffuse noxious inhibitory controls (DNIC) and conditioned pain modulation (CPM), respectively, whereby one painful stimulus can inhibit another11. This control mechanism often fails in persistent pain states, allowing descending facilitation from the rostral ventromedial medulla (RVM) to dominate.
A potential paradigm shift in opioid crisis management: The role of pharmacogenomics
Published in The World Journal of Biological Psychiatry, 2022
David Eapen-John, Ayeshah G. Mohiuddin, James L. Kennedy
Opioids and opiates are a class of analgesic drugs widely used in a clinical setting for pain management, especially in the post-operative context. Opioid class drugs target both the ascending (sensory) and descending (modulatory) pain pathways to produce analgesia. At the level of the brainstem, opioids act on GABAergic interneurons in the Periaqueductal Grey (PAG) to disinhibit the antinociceptive activity of projection neurons to the rostral ventromedial medulla (RVM) which blocks the ascending transmission of pain signals from the spinal cord (Jalabert et al. 2011; Matsui et al. 2014; Owusu Obeng et al. 2017; Burns et al. 2019). At the level of the spinal cord, opioids act on pain transmission neurons in the dorsal horn, reducing their activity and subsequently the ascending transmission of nociceptive signals (Jalabert et al. 2011; Matsui et al. 2014; Owusu Obeng et al. 2017; Burns et al. 2019).
Related Knowledge Centers
- Myelencephalon
- Nociception
- Medulla Oblongata
- Spinal Cord
- Animal Embryonic Development
- Posterior Grey Column
- Neuron
- Μ-Opioid Receptor
- Dermorphin
- Saporin