The Role of the Subnucleus Reticularis Dorsalis (SRD) in Pain Modulation: A Literature Review

Abstract

The subnucleus reticularis dorsalis (SRD), also known as the dorsal reticular nucleus (DRt) or dorsal medullary reticular nucleus (MdD), which resides at the caudal end of the medulla, plays a pivotal role in regulating pain perception. Despite extensive research efforts to unravel its mechanisms, the operational intricacies of SRD remain poorly understood. Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders. This comprehensive review aims to analyze 36 years (1989–2024) of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, and its interconnected neural circuits. Moreover, this review explores the neural circuits related to SRD, including locus coeruleus (LC)-SRD, parabrachial nucleus (PBN)-SRD, rostroventromedial medulla (RVM)-ventrolateral medulla (VLM)-SRD, anterior cingulate cortex (ACC)-SRD, medial medullary reticular formation (mMRF)-SRD, and dorsal striatum (DS)-SRD. Their activation also plays a significant role in analgesia. The pivotal roles of neurotransmitters such as μ-opioid receptor (MOR), noradrenaline, and metabotropic glutamate receptor 7 (mGluR7) in modulating SRD responsiveness to pain stimuli are also discussed, as are the influences of SRD on different pain types. This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.

Keywords

SRD / DNIC / Pain modulation / Descending modulation pathways / Neural circuits / Neurotransmitters

References

[1] MillsEP, KeayKA, HendersonLA. Brainstem Pain-Modulation Circuitry and Its Plasticity in Neuropathic Pain: Insights From Human Brain Imaging Investigations. Front Pain Res (Lausanne), 2021, 2. 705345

[2] DugastC, AlmeidaA, LimaD. The medullary dorsal reticular nucleus enhances the responsiveness of spinal nociceptive neurons to peripheral stimulation in the rat. Eur J Neurosci, 2003, 18(3): 580-588.

[3] MartinsI, TavaresI. Reticular Formation and Pain: The Past and the Future. Front Neuroanat, 2017, 1151.

[4] DesboisC, Le BarsD, VillanuevaL. Organization of cortical projections to the medullary subnucleus reticularis dorsalis: a retrograde and anterograde tracing study in the rat. J Comp Neurol, 1999, 410(2): 178-196.

[5] BarikA, ThompsonJH, SeltzerM, et al.. A brainstem-spinal circuit controlling nocifensive behavior. Neuron, 2018, 100(6): 1491-1503 e1493.

[6] LiM, SheK, ZhuP, et al.. Chronic Pain and Comorbid Emotional Disorders: Neural Circuitry and Neuroimmunity Pathways. Int J Mol Sci, 2025, 262436.

[7] BernardJF, VillanuevaL, CarroueJ, et al.. Efferent projections from the subnucleus reticularis dorsalis (SRD): a Phaseolus vulgaris leucoagglutinin study in the rat. Neurosci Lett, 1990, 116(3): 257-262.

[8] VillanuevaL, de PommeryJ, MenetreyD, et al.. Spinal afferent projections to subnucleus reticularis dorsalis in the rat. Neurosci Lett, 1991, 134(1): 98-102.

[9] VillanuevaL, BingZ, BouhassiraD, et al.. Encoding of electrical, thermal, and mechanical noxious stimuli by subnucleus reticularis dorsalis neurons in the rat medulla. J Neurophysiol, 1989, 61(2): 391-402.

[10] VillanuevaL, BouhassiraD, Le BarsD. The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals. Pain, 1996, 67(2–3): 231-240.

[11] RoyJC, BingZ, VillanuevaL, et al.. Convergence of visceral and somatic inputs onto subnucleus reticularis dorsalis neurones in the rat medulla. J Physiol, 1992, 458: 235-246.

[12] BingZ, VillanuevaL, Le BarsD. Ascending pathways in the spinal cord involved in the activation of subnucleus reticularis dorsalis neurons in the medulla of the rat. J Neurophysiol, 1990, 63(3): 424-438.

[13] Le BarsD, VillanuevaL, BouhassiraD, et al.. Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter., 1992, 4: 55-65

[14] VillanuevaL, Le BarsD. The activation of bulbo-spinal controls by peripheral nociceptive inputs: diffuse noxious inhibitory controls. Biol Res, 1995, 28(1): 113-125

[15] VillanuevaL, DesboisC, Le BarsD, et al.. Organization of diencephalic projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a retrograde and anterograde tracer study in the rat. J Comp Neurol, 1998, 390(1): 133-160.

[16] SotoC, Martin-CoraFJ, LeirasR, et al.. Processing noxious information at the subnucleus reticularis dorsalis (SRD) of anesthetized cats: wind-up mechanisms. Pain, 2008, 140(1): 190-208.

[17] TsuruokaM, HirumaY, WillisWD. The subnucleus reticularis dorsalis is involved in antinociception produced by a low dose of naloxone during carrageenan-induced inflammation. Brain Res, 1997, 762(1–2): 264-268.

[18] PatelR, DickensonAH. A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats. Eur J Neurosci, 2020, 51(4): 952-962.

[19] YoussefAM, MacefieldVG, HendersonLA. Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans. Hum Brain Mapp, 2016, 37(7): 2630-2644.

[20] LeoneC, TruiniA. The CPM Effect: Functional Assessment of the Diffuse Noxious Inhibitory Control in Humans. J Clin Neurophysiol, 2019, 36(6): 430-436.

[21] RempeT, WolffS, RiedelC, et al.. Spinal and supraspinal processing of thermal stimuli: an fMRI study. J Magn Reson Imaging, 2015, 41(4): 1046-1055.

[22] RempeT, WolffS, RiedelC, et al.. Spinal fMRI reveals decreased descending inhibition during secondary mechanical hyperalgesia. PLoS One, 2014, 911. e112325

[23] YoussefAM, MacefieldVG, HendersonLA. Pain inhibits pain; human brainstem mechanisms. Neuroimage, 2016, 124(Pt A): 54-62.

[24] LeirasR, Martin-CoraF, VeloP, et al.. Cat’s medullary reticulospinal and subnucleus reticularis dorsalis noxious neurons form a coupled neural circuit through collaterals of descending axons. J Neurophysiol, 2016, 115(1): 324-344.

[25] AmorimD, ViisanenH, WeiH, et al.. Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways. PLoS One, 2015, 1011. e0142919

[26] Camarena-DelgadoC, Llorca-TorralbaM, Suarez-PereiraI, et al.. Nerve injury induces transient locus coeruleus activation over time: role of the locus coeruleus-dorsal reticular nucleus pathway. Pain, 2022, 163(5): 943-954.

[27] MartinsI, CarvalhoP, de VriesMG, et al.. Increased noradrenergic neurotransmission to a pain facilitatory area of the brain is implicated in facilitation of chronic pain. Anesthesiology, 2015, 123(3): 642-653.

[28] ShiW, XueM, WuF, et al.. Whole-brain mapping of efferent projections of the anterior cingulate cortex in adult male mice. Mol Pain, 2022, 1817448069221094529.

[29] Leite-AlmeidaH, Valle-FernandesA, AlmeidaA. Brain projections from the medullary dorsal reticular nucleus: an anterograde and retrograde tracing study in the rat. Neuroscience, 2006, 140(2): 577-595.

[30] BoccellaS, MarabeseI, GuidaF, et al.. The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum. Curr Neuropharmacol, 2020, 18(1): 34-50.

[31] LimaD, AlmeidaA. The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system. Prog Neurobiol, 2002, 66(2): 81-108.

[32] CostaAR, CarvalhoP, FlikG, et al.. Neuropathic Pain Induced Alterations in the Opioidergic Modulation of a Descending Pain Facilitatory Area of the Brain. Front Cell Neurosci, 2019, 13287.

[33] MartinsI, PintoM, WilsonSP, et al.. Dynamic of migration of HSV-1 from a medullary pronociceptive centre: antinociception by overexpression of the preproenkephalin transgene. Eur J Neurosci, 2008, 28(10): 2075-2083.

[34] PintoM, CastroAR, TshudyF, et al.. Opioids modulate pain facilitation from the dorsal reticular nucleus. Mol Cell Neurosci, 2008, 39(4): 508-518.

[35] WilliamsJT, IngramSL, HendersonG, et al.. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev, 2013, 65(1): 223-254.

[36] El KouhenR, BurdAL, Erickson-HerbrandsonLJ, et al.. Phosphorylation of Ser363, Thr370, and Ser375 residues within the carboxyl tail differentially regulates mu-opioid receptor internalization. J Biol Chem, 2001, 276(16): 12774-12780.

[37] Martinez-NavarroM, MaldonadoR, BanosJE. Why mu-opioid agonists have less analgesic efficacy in neuropathic pain?. Eur J Pain, 2019, 23(3): 435-454.

[38] CostaAR, SousaM, WilsonSP, et al.. Shift of micro-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats. Anesthesiology, 2020, 133(3): 628-644.

[39] CrainSM, ShenKF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain, 2000, 84(2–3): 121-131.

[40] CostaAR, TavaresI, MartinsI. How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain. Pain, 2024, 165(2): 324-336.

[41] MarabeseI, BoccellaS, IannottaM, et al.. Metabotropic glutamate receptor subtype 7 in the dorsal striatum oppositely modulates pain in sham and neuropathic rats. Neuropharmacology, 2018, 135: 86-99.

[42] TavaresI, Costa-PereiraJT, MartinsI. Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?. Front Pain Res (Lausanne), 2021, 2. 696515

[43] de ResendeMA, SilvaLF, SatoK, et al.. Blockade of opioid receptors in the medullary reticularis nucleus dorsalis, but not the rostral ventromedial medulla, prevents analgesia produced by diffuse noxious inhibitory control in rats with muscle inflammation. J Pain., 2011, 12(6): 687-697.

[44] Pereira-SilvaR, Teixeira-PintoA, NetoFL, et al.. μ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats. Anesthesiology, 2024, 140(6): 1176-1191.

[45] YuL, LiL, QinQ, et al.. Electroacupuncture Inhibits Visceral Nociception via Somatovisceral Interaction at Subnucleus Reticularis Dorsalis Neurons in the Rat Medulla. Front Neurosci, 2018, 12775.

Funding

Key Program of the National Natural Science Foundation of China (No.82130122).(2950000RMB)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to Huazhong University of Science and Technology