Part I: Skin Deep – The Role of Endocannabinoid System in Cutaneous Below the epidermis lies the dermis, a layer composed of the fibrillar structural protein of proliferation and migration, sending cells towards the surface of the skin to. Jun 10, In the skin, cannabinoid lipids, whether of endogenous or . As detailed below, however, the ability of cannabinoids to evoke pain under Thus, endocannabinoids and their receptors constitute part of an adaptive system to regulate .. TRPV2 both by promoting its translocation to the cell surface and by . Finally, the therapeutic potential of the endocannabinoid signaling system is discussed .. in different layers of the skin, and in some adnexal structures ( sweat glands, of acute, inflammatory and neuropathic pain models are reviewed below. . onto the plantar surface of the paw through the floor of a glass platform .
and Your the System The Surface: Skin Beneath Endocannabinoid
Novel clusters of receptors for sphingosinephosphate, sphingosylphosphorylcholine, and lyso -phosphatidic acid: Fluid shear stress differentially regulates gpr3, gpr6, and gpr12 expression in human umbilical vein endothelial cells. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Inhibition of human recombinant T-type calcium channels by the endocannabinoid N-arachidonoyl dopamine.
The expanding field of cannabimimetic and related lipid mediators. Targeting the endocannabinoid system: A new perspective on N-acylethanolamines as neural signaling molecules. Molecular characterization of a phospholipase D generating anandamide and its congeners. Biosynthetic pathways of the endocannabinoid anandamide. Inactivation of N-acylphosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids.
Multiple pathways involved in the biosynthesis of anandamide. Critical enzymes involved in endocannabinoid metabolism. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages.
The molecular logic of endocannabinoid signalling. The ligand that came from within. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor hVR1 Br. A second endogenous cannabinoid that modulates long-term potentiation. An endocannabinoid mechanism for stress-induced analgesia. Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia.
Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Anandamide and vanilloid TRPV1 receptors. Endovanilloid signaling in pain. Cannabinoid 1 receptors are expressed in nocceptive primary sensory neurons. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain.
Functional role of high-affinity anandamide transport, as revealed by selective inhibition. The endocannabinoid system and its therapeutic exploitation.
Accumulation of N-arachidonoylethanolamine anandamide into cerebellar granule cells occurs via facilitated diffusion. Hillard CJ, Jarrahian A.
Cellular accumulation of anandamide: Identification of a high-affinity binding site involved in the transport of endocannabinoids. Biosynthesis, uptake and degradation of anandamide and palmitoylethanolamide in leukocytes. The movement of N -arachidonolethanolamide anandamide across cellular membranes. Anandamide uptake by human endothelial cells and is regulation by nitric oxide. Retrograde signaling in the regulation of synaptic transmission: Role of endogenous cannabinoids in synaptic signaling.
Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Endocannabinoid signaling in the brain. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Seierstad M, Breitenbucher JG. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.
Molecular characterization of human and mouse fatty acid amide hydrolases. Brain monoglyceride lipase participating in endocannabinoid inactivation. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Formation and inactivation of endogenous cannabinoid anandamide in central neurons.
A new perspective on cannabinoid signaling: Comparative analysis of fatty acid amide hydrolase and CB 1 cannabinoid receptor expression in the mouse brain: Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand.
Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. The complications of promiscuity: Guindon J, Hohmann AG. A physiological role for endocannabinoid-derived products of cyclooxygenasemediated oxidative metabolism. Endocannabinoid metabolism and uptake: Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity. The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action.
Anandamide metabolism by human liver and kidney microsomal cytochrome p enzymes to form hydroxyeicosatetraenoic and epoxyeicosatrienoic acid ethanolamides. Characterization and localization of cannabinoid receptors in rat brain: Spinal and peripheral mechanisms of cannabinoid antinociception: Cannabinoid mechanisms of pain suppression. Spinal and supraspinal components of cannabinoid-induced antinociception. Intrathecal cannabinoid administration suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in rat spinal cord: Investigation of brain sites mediating cannabinoid induced antinociception in rats: An examination of the central sites of action of cannabinoid-induced antinociception in the rat.
Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla.
An analgesia circuit activated by cannabinoids. The endogenous cannabinoid system controls extinction of aversive memories. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55, Pain modulation by release of the endogenous cannabinoid anandamide. Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats.
Neuropathic pain and the endocannabinoid system in the dorsal raphe: Effect of repeated systemic administration of selective inhibitors of endocannabinoid inactivation on rat brain endocannabinoid levels. Spinal mechanisms of delta 9-tetrahydrocannabinol-induced analgesia. Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat.
Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55, Cannabinoid agonist, CP 55,, prevents capsaicin-induced sensitization of spinal cord dorsal horn neurons. Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. Upregulation of spinal cannabinoidreceptors following nerve injury enhances the effects of Win 55,— on neuropathic pain behaviors in rats.
Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation.
Cannabinoid WIN 55, inhibits the activity-dependent facilitation of spinal nociceptive responses. Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB 1 and CB 2 -like receptors. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Selective activation of cannabinoid CB 2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.
Suppression of noxious stimulus-evoked expression of Fos protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neuronal and astrocytic localization of the cannabinoid receptor-1 in the dorsal horn of the rat spinal cord.
The endocannabinoid system is modulated in response to spinal cord injury in rats. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: Distribution of cannabinoid receptor 1 CB1 and 2 CB2 on sensory nerve fibers and adnexal structures in human skin. Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: Peripheral mechanisms of inflammatory pain: Recent advances in anaesthesia and analgesia. Neuronal control of skin function: Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain.
Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain.
Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. Guindon J, Beaulieu P. The role of the endogenous cannabinoid system in peripheral analgesia.
CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Control of pain initiation by endogenous cannabinoids.
Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. SR A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice.
Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia. Move so it appears numerically between and A method for determining the loss of pain sensation. Hasanein P, Javanmardi K. A potent and selective inhibitor of endocannabinoid uptake, UCM, potentiates antinociception induced by cholestasis.
Assessment of anandamide interaction with the cannabinoid brain receptor: SR A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase.
The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice. SR A, a cannabinoid receptor antagonist, reverses the behavioural effects of anandamide-treated rats.
Cannabinoid modulation of dynorphin A: Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SRA. Pharmacological actions of cannabinoids. The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the pharmacological effect of anandamide in the mouse model of cannabimimetic activity.
Effects of URB as an inhibitor of fatty acid amide hydrolase on modulation of nociception in a rat model of cholestasis. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. UCM, a potent and selective inhibitor of endocannabinoid uptake, potentiates hypokinetic and antinociceptive effects of anandamide. In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake.
Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Characterization of anandamide-and fluoroanandamide-induced antinociception and cross-tolerance to delta 9-THC after intrathecal administration to mice: Modulation of anxiety through blockade of anandamide hydrolysis. Novel inhibitors of fatty acid amide hydrolase. Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats.
A method for measurement of analgesic activity on inflamed tissue. Dubuisson D, Dennis SG. Coderre TJ, Katz J. Peripheral and central hyperexcitability: Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury.
Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM [N- 4-hydroxyphenyl -eicosa-5,8,11,tetraenamide] J. Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain.
The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors. Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors.
New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain. The antinociceptive effects of local injections of propofol in rats are mediated in part by cannabinoid CB1 and CB2 receptors.
What is becoming more and more evident to modern day scientists is that, when used synergistically together, they offer one of the most effective ways of improving the human health. Interestingly, it appears that it is not just acupuncture that kindles the endocannabinoid system ECS , but cannabis does that as well. CB1 receptors occur mostly in the brain of almost all mammals while CB2 is present in the body tissues, organs and throughout the central nervous system.
Basically, the ECS is known to regulate everything from immune system responses, pain sensations and inflammation to appetite, mood, memory, as well as overall metabolism. Like marijuana, acupuncture appears to kindle the body in various ways, working to heal, optimize, and heal major systems of the body, including, the endocannabinoid system.
The science being acupuncture explains that the analgesic, pain-alleviating effects of inserting needles just beneath the human skin in key points, basically, does something other than making the patient look like a porcupine. Interestingly, when these are released via the placement of tiny needles, pain and inflammation ease a bit.
As acupuncture starts to help the damaged body areas to function better, it also stirs up the endocannabinoid system with an aim of regulating the body and controlling pain.
And so, in the future, it is highly likely that research will study not only at how acupuncture stirs up the ECS but also how medical cannabis itself can help to maintain such stimulations or triggers, even between treatments, to restore damaged systems to optimal health. Acupuncture boasts of numerous success stories of assisting patients to lose weight, regain health and free themselves from addictions. Finally, cutaneous TRPV1 expression levels change in some human dermatological conditions.
Another TRP channel target of cannabinoids is transient receptor potential ankyrin 1 TRPA1 , so-named because of the existence of 16 ankyrin repeats in its amino terminal domain. Most of the identified TRPA1 agonists are irritant electrophiles such as allyl isothiocyanate mustard oil , cinnamaldehyde, and formaldehyde. Electrophiles activate TRPA1 by covalently alkylating intracellular cysteine residues located among the ankyrin repeats.
TRPA1 can alternatively be activated by noncovalent chemical agonists. TRPA1 participates in both acute pain sensation and hyperalgesia. Pain related responses triggered by covalent TRPA1 agonists are reduced by pharmacological antagonism of TRPA1 or by genetic deletion of this channel in mice. This results in part from sensory neuron-expressed TRPA1 acting downstream of signaling by G protein-coupled receptors for itch-producing peptides or monoamines.
TRPA1 agonists produce robust neurogenic inflammation in skin, which can be ablated by either pharmacological antagonism or genetic elimination of TRPA1. Oxa increased skin expression of 4-hydroxynonenol, providing a potential means of TRPA1 activation in this model.
Furthermore, TRPA1 knockout mice exhibited reduced epidermal thickening and reduced skin expression of inflammatory cytokines in this model. For example, in the acetone—ether—water model of chronic dry skin, genetic elimination of TRPA1 not only diminished itch-related behavioral responses, but also suppressed epidermal thickening and the cutaneous upregulation of numerous genes, including keratin 6, aquaporin 3, and IL Neurogenic mechanisms undoubtedly account for some of the proinflammatory cutaneous effects of TRPA1 described above.
This raises the possibility that alterations in inflammatory responses in TRPA1 knockout mice might additionally reflect changes in the innate immune responses of these cells.
Although TRPA1 and TRPV1 are capable of functioning as independent channels, they are coexpressed in a subset of peripheral sensory neurons, and growing evidence suggests that these channels can functionally interact. The mechanisms underlying this reciprocal cross-desensitization are complex, and likely not identical. TRPA1 and TRPV1 can bind to one another, though whether this binding involves the formation of heterotetramers versus binding between two different homotetrameric channels remains unclear.
Regardless, the functional interaction of TRPV1 and TRPA1 offers a potential mechanism by which cannabinoids might regulate not only pain and itch perception, but also cutaneous inflammation. AlthoughTRPV2 is robustly expressed in peripheral sensory neurons, 62 extensive examination of pain responses in TRPV2 knockout mice failed to reveal an obvious role for this channel in thermal or mechanical nociception. TRPV2 might participate in neurogenic inflammation. Thus, while there is abundant circumstantial evidence of TRPV2 involvement in skin biology, more studies will be necessary to clearly define any such roles.
TRPV3 knockout mice were initially observed to exhibit a prolonged latency to heat-evoked behavioral withdrawal and to exhibit delayed selection of preferred temperatures on a thermal gradient. Pain and itch arising from genetic mutation of TRPV3 in humans is discussed below. Studies of both global and keratinocyte-specific TRPV3 knockout mice have revealed that this channel is critical for normal epidermal differentiation and hair morphology.
Late embryonic TRPV3 knockout mice exhibited premature epidermal differentiation, compromised epidermal barrier function, abnormal corneocytes, and reduced epidermal transglutaminase activity. Many of these changes appeared to resolve over time. In addition, throughout life, TRPV3 knockout mice exhibited curly whiskers and abnormalities in body fur. TRPV3 activation has also been reported to inhibit growth of human hair.
Point mutations in TRPV3 can have profound effects on skin. Genetic background also influenced the ability of the Gly Ser mutation to augment the predilection of mice toward chemically evoked allergic contact dermatitis. Strikingly, the ability of mutations at TRPV3 Gly to cause dermatological disease is not confined to rodents. Using whole exome sequencing, Lin et al. These histological changes are typically accompanied by intense itching.
Hair loss and deformities of the digits, including autoamputation, are also observed in some individuals. The Olmsted-associated human TRPV3 mutant variants, like the homologous rodent mutants, exhibited robust spontaneous activity when transfected into cell lines.
These mutants also triggered apoptosis in transfected cells, and, accordingly, histological examination revealed an increase in apoptosis in skin from Olmsted syndrome patients.
Some of the affected patients experienced not only plantar keratoderma, but also erythromelalgia, an intermittent reddening of the skin accompanied by intense pain, itch, warmth, and vasodilation.
Whether endogenous cannabinoids contribute to the pathophysiology of these conditions, or whether exogenous cannabinoids might be useful to treat patients with TRPV3 mutations, remains to be determined. It is also not yet clear whether abnormalities in TRPV3 sequence, expression, or regulation might lead to other dermatological diseases. There is also evidence for TRPV4 expression in both sensory and motor neurons.
TRPV4 was originally identified as a channel that could be gated by changes in osmolarity. Recently, two phytocannabinoids, cannabidivarin and tetrahydrocannabivarin, were shown to stimulate TRPV4, while cannabigerovarin, cannabigerolic acid, cannabinol, and cannabigerol were shown to desensitize this channel 81 Table 1.
Multiple lines of evidence support a role for TRPV4 in pain sensation. TRPV4 knockout mice were found to exhibit reduced acute mechanically evoked pain behaviors. One possible contributor to this phenotype was the absence of TRPV4-dependent synthesis and release of endothelin 1 from UVB treated keratinocytes.
TRPV4 appears to be important for the temperature-dependent formation of normal epithelial tight junctions between skin keratinocytes in both mice and humans. This function involves TRPV4-dependent calcium entry, with subsequent activation of Rho kinases and actin rearrangement. Mice lacking TRPV4 were reported to exhibit impaired epidermal barrier function.
They also exhibited a thickened stratum corneum, perhaps as a reaction to the former deficit. For example, the keratinocyte-selective knockout of the TRPV4 gene not only reduces pain arising from UVB irradiation, but also suppresses irradiation induced skin damage and inflammatory cell recruitment.
In mice, this channel is essential for cutaneous discrimination of mildly cold temperatures, and also appears to play both positive and negative roles in cold-evoked pain sensation. Immunoreactivity for TRPM8 has been demonstrated in human skin, and is reduced in patients with congenital insensitivity to pain. In summary, cannabinoids can engage numerous targets within the skin, including not only metabotropic receptors, but also multiple members of the TRP family of ion channels.
Cutaneous ionotropic cannabinoid receptors participate in functions related to pain and itch perception, epidermal homeostasis, and the promotion and suppression of dermatitis in both animal models and humans. This situation creates potential opportunities to intervene therapeutically in sensory and inflammatory skin diseases using the chemically rich pharmacology of cannabinoids.
In addition, the experimental accessibility of the skin makes this organ an excellent one in which to uncover principles of intercellular cannabinoid signaling that may be generalizable to the CNS and other less accessible tissues.
The Endocannabinoid System and Pain
Jan 17, The endocannabinoid system consists of cellular receptors found in very large . what type of cell it is—nerve cells, immune cells, skin cells, muscle cells, secretory cells Below are a few interesting facts about the ECS in general: . to eat them, and, subsequently, spreading the spores to nearby surfaces. Skin Care Classes Meditation GIFT CERTIFICATES & PACKAGES Plan Your Visit The body's endocannabinoid system (ECS) is a vital molecular system for Cannabinoid receptors sit on the surface of cells and “listen” to conditions outside the cell. Below we will consider examples of how the ECS helps maintain. Oct 4, Let's explore the magic that hides beneath the popular surface of cannabis. the endocannabinoid system is the ultimate balance system of our . as an appetite stimulant, an antibacterial for skin infections, a cancer cell.