Pharmacogn J. 2021; 13(1): 248-263 A Multifaceted Journal in the field of Natural Products and Pharmacognosy Review Article www.phcogj.com Potential Activity of Medicinal Plants as Pain Modulators: A Review Carmen R. Silva-Correa1,*, Jorge L. Campos-Reyna2, Víctor E Villarreal-La Torre1, Abhel A. Calderón-Peña3, María V. González Blas1, Cinthya L. Aspajo-Villalaz3, José L. Cruzado-Razco1, William Antonio Sagástegui- Guarniz1, Luz M. Guerrero-Espino2, Julio Hilario-Vargas2 ABSTRACT This review aims to demonstrate the relevance that medicinal plants and their promising results have in prevention and treatment of pain. The neurophysiological bases of pain have been analyzed and the potential mechanisms of action have been proposed, it has also been Carmen R. Silva-Correa1,*, determined that the main experimental models used for the evaluation of the analgesic Jorge L. Campos-Reyna2, Víctor potential are: acetic acid-induced writhing test, formalin test, hot-plate test, capsaicin-induced E Villarreal-La Torre1, Abhel nociception, cinnamaldehyde-induced nociception, glutamate-induced nociception, tail–flick A. Calderón-Peña3, María V. test and tail immersion test. There are countless medicinal plants with potential analgesic González Blas1, Cinthya L. Aspajo- activity, in some of them main responsible compounds for the activity are flavonoids (vitexin, Villalaz3, José L. Cruzado-Razco1, quercetin, naringenin, astragalin, eupatilin), alkaloids (scotanamine B, bullatine A, S-(+)- William Antonio Sagástegui- dicentrine, stephalagine, lappaconitine), terpenoids (p-cymene, thymol, menthol, citronellol, Guarniz1, Luz M. Guerrero- myrcene, carvacrol, linalool) and saponins (siolmatroside I, cayaponoside D, cayaponoside B4, Espino2, Julio Hilario-Vargas2 cayaponoside A1); however, all studies have only been carried out up to pre-clinical stages. Therefore, it is recommended to carry out kinetic studies of the most remarkable natural 1Facultad de Farmacia y Bioquímica, Universidad Nacional de Trujillo, PERÚ. compounds, evaluate mixtures of active compounds for diminishing doses to avoide possible 2Facultad de Medicina, Universidad Nacional side effects, and continue with clinical studies of medicinal plants whose safety has already de Trujillo, PERÚ. been reported. 3Facultad de Ciencias Biológicas, Universidad Key Words: Pain, Analgesic, Antinociceptive, Natural product, Extract. Nacional de Trujillo, PERÚ.. Correspondence INTRODUCTION being associated with adverse effects and use of Carmen R. Silva-Correa opioid drugs, in most of the patients have generated Affiliation: Facultad de Farmacia y Although pain is a defense mechanism, that acts as addiction and its excessive use even produced death Bioquímica, Universidad Nacional de an alarm signal to protect the organism and extend 5 Trujillo, PERÚ. by overdose. the human survival, it is considered one of the most E-mail: [email protected] important public health problems in the world, Classic analgesic drugs such as morphine, codeine especially chronic pain that is still an important and aspirin have been isolated from natural products, History challenge of modern medicine.1,2 The International which has attracted the attention of many researchers • Submission Date: 05-09-2020; Association for the Study of Pain (IASP), defines it as a source that could provide the discovery of new • Review completed: 12-10-2020; as an unpleasant sensory and emotional experience analgesic drugs.5,7 In addition, medicinal plants • Accepted Date: 26-10-2020. associated with actual or potential tissue damage.3 and their metabolites have a reduced number of DOI : 10.5530/pj.2021.13.35 side effects and they are used as an unexpensive Pain is a dynamic phenomenon that is characterized therapeutic resources for management of chronic Article Available online by going from the periphery to the brain and the pain.2,8 http://www.phcogj.com/v13/i1 nociceptive signal is modulated at every level of 4 Copyright Central Nervous System (CNS). A disease or Evaluation of medicinal plants on pain has been © 2021 Phcogj.Com. This is an open- injury at the Central Nervous System (CNS) or studied using different experimental models access article distributed under the terms at the Peripheral Nervous System (PNS) causes including writhing test, light tail movement test, of the Creative Commons Attribution 4.0 a potential risk to the body, whose will activate tail immersion test, hot plate test and formalin International license. free nerval terminals in response to nociceptive test.9 Results obtained in these tests show that most stimulation.3 Most of these nervous fibers are important secondary metabolites with analgesic polymodal and will respond to mechanical, thermal effect include flavonoids, volatile oils, phenolic and chemical stimulation.2,4 compounds and alkaloids.10 Non-opioid drugs have been used in treatment Despite actual pain treatments, they reduces the of mild to moderate pain, while opioid drugs quality of life, increases health costs and generates are used in the treatment of moderate pain.5 economic losses to society, either due to mechanical, Conventional therapy for neuropathic pain inflammatory or neuropathic pain from a disease includes: non-steroidal anti-inflammatoryor injury to nervous system.11 That is the reason drugs (ketorolac), opioids (morphine), tricyclic of the importance of continuing with the search antidepressants (amitriptyline, duloxetine), and for new analgesic compounds that supplement or some anticonvulsants (gabapentin);6 however, all enrich preexisting alternatives. Throughout history, these drugs have shown moderate efficacy, often multiple natural extracts have been studied as Cite this article: Silva-Correa CR, Campos-Reyna JL, Villarreal-La Torre VE, Calderón-Peña AA, González Blas MV, Aspajo-Villalaz CL, et al. Potential Activity of Medicinal Plants as Pain Phcogj.com Modulators: A Review. Pharmacog J. 2021;13(1): 248-63. 248 Pharmacognosy Journal, Vol 13, Issue 1, Jan-Feb, 2021 Silva-Correa, et al.: Potential Activity of Medicinal Plants as Pain Modulators: A Review sources of active ingredients with analgesic activity, many of them with expression of sodium channels thus facilitating the generation and great potential to continue in the search for new chemical entities that transmission of stimuli; This is called peripheral sensitization, which become candidates for new drugs aimed at controlling pain syndromes. lowers the nociceptive threshold and facilitates noxious responses to promote adequate tissue recovery; this is the pathophysiological basis This review aims to enhance the rol of medicinal plants and their of acute pain.21 promising results for the prevention and treatment of pain. Indeed, the neurophysiological bases of pain will be analyzed first, for allowing us Pain modulation can lead to increased transmission of pain impulses to predict possible mechanisms of the natural compounds reported as (facilitation) or decreased transmission (inhibition). Balance between potential pain modulators. these states ultimately determines the quality and strength of the pain signals that lead to the perception of pain in the brain. Alterations in the NEUROPHYSIOLOGICAL BASES OF PAIN state of the descending modulatory pathways toward facilitation have 27 From the neurophysiological point of view, perception of pain requires been associated with the transition from acute to chronic pain. participation of the CNS and the PNS, triggering a series of reactions Sensitization of peripheral nociceptors underlies hyperalgesia that in both systems that allow the perception of it, in order to reduce the develops immediately around the injury site; afferent fibers can be cause and limit the consequences.1 Pain is classified as acute or chronic, sensitized by endogenous chemicals. This results in an increase in their nociceptive or neuropathic and, depending on the driving speed, fast or responsiveness to a given stimulus and/or an increase in spontaneous slow. Stimuli that cause pain are detected by nociceptor receptors and activity.28 In addition, during inflammation an upregulated expression of free nerve terminals that respond to painful stimuli and communicate nociceptors such as sodium channels is observed, receptors of transient nociceptive information through C fibers and Aδ fibers.12-13 potential (TRPV1), pH detection ion channels (ASIC) and purinergic In neural process of pain transmission, transduction is considered, receptors (P2X). As a consequence of all these changes, sensitivity to 29 which is the conversion of nociceptive stimulus into an electrical signal pain at the site of inflammation increases. in the nociceptors; transmission, when pain stimuli are referred to the Central sensitization with enhanced spinal information of inflammation dorsal horn of the spinal cord and pain neurotransmitters are released can activate intracellular signaling cascades within neurons of the spinal (Glutamate, substance P, peptide related to the calcitonin gene) and; dorsal horn, this results in increased synaptic efficiency and is known modulation, which is the pain signal in the dorsal horn of the spinal as central sensitization Deep pain and visceral pain input to spinal cord cord that can be inhibited and modified for supra pain centers.12,14 In are more potent than cutaneous pain in inducing central sensitization.30 conclusion, the stimuli are transmitted to the spinal cord, by nerve Entry leads to activation of the N-methyl-D-aspartic acid receptor and fibers, and then travel later