Insight into the proteins in the brain that detect cannabis
April 30, 2019
Science Daily/University of Bristol
Researchers at the University of Bristol have made new progress in understanding how cannabinoid receptors (CB1Rs), the proteins that detect the active components of marijuana, are controlled in the brain.
The brain contains about 100 billion nerve cells that are constantly communicating with one another at specialised junctions called synapses. Nerve cells possess extensions called axons, which send signals to synapses, and dendrites, which receive information from synapses.
At the synapse, the electrical 'firing' of a nerve cell causes the release of chemicals called neurotransmitters from the presynaptic terminals of its axon. These neurotransmitters cross the synapse and pass on the signal by binding to receptors at postsynaptic sites on the dendrites of the next nerve cell.
CB1Rs help control information flow in the brain by binding molecules made in the brain called endocannabinoids, which influence brain functions such as pain, appetite, mood and memory. Unusually, endocannabinoid signalling goes in the reverse direction compared to most other neurotransmitters. The 'receiving' CB1Rs are located at presynaptic sites on axons, whereas the release sites are at postsynaptic sites on dendrites.
This reverse or 'retrograde' signalling that activates presynaptic CB1Rs 'dampens down' presynaptic release of other neurotransmitters resulting in a slowing of brain activity. Moreover, the active components of cannabis bind to CB1Rs in a similar manner to endocannabinoids, resulting in the 'mellow' sensation caused by the recreational use of cannabis.
For CB1Rs to regulate brain function properly, it is essential that they are sent to the right place on the surface of the axon. However, very little is known about exactly how this occurs. The research published today [Tuesday 30 April] in eLife investigated how this process happens.
The Bristol group showed that a specific part of the CB1R protein plays a key role in the getting CB1R into axons. The research team tracked newly made CB1Rs in nerve cells grown in a dish and found that a short region of CB1R is crucial for sending CB1R to the axon and preventing it from going to the dendrites. They also discovered that this region stabilises CB1R at the surface of the axon, making it more available to receive signals from endocannabinoids.
Jeremy Henley, Professor of Molecular Neuroscience in Bristol's School of Biochemistry, said: "In recent years there has been tremendous interest in -- and controversy about -- activation of CB1R by medical marijuana. It is becoming increasingly apparent that activation of CB1Rs could be therapeutically useful for a wide range of diseases such as chronic pain, epilepsy, or multiple sclerosis. Understanding the fundamental properties of CB1R is an important basis for future studies exploring the efficacy and optimisation of these targeted approaches."
It is hoped that this increased understanding of how CB1Rs behave in nerve cells will pave the way for future studies aimed at examining the possible medical uses of marijuana, or other drugs that target CB1Rs, in treating a wide range of disorders.
https://www.sciencedaily.com/releases/2019/04/190430103457.htm
Opioids and Cannabinoids Influence Mobility of Spermatozoids
June 24, 2008
Science Daily/Basque Research
A PhD thesis from the University of the Basque Country has concluded that there are opioid and cannabinoid receptors in human sperm and that these influence the mobility of spermatozoid. The research by Mr Ekaitz Agirregoitia opens the door to more effective treatment of fertility problems.
Freshly released spermatozoids cannot achieve fertilisation, they must undergo some changes for this to occur. Amongst other, such changes take place due to receptors situated in the plasmatic membrane (the layer covering the cells) and opioid and cannabinoid receptors are two of these. On coming into contact with these, physiological reactions are generated in the body which are similar to, for example, sedation, analgesia and low blood pressure. Moreover, according to the research undertaken to date, both substances have an influence on the process of fertilisation.
It is known that the consumption of external opiates (heroin, methadone) reduces the mobility of spermatozoids and that external cannabinoids (hachis) causes changes in the reproductive process. Also, the body itself generates internal opioids and cannabinoids, secreted to enable us withstand pain or stress situations, and it is also known that this phenomenon affects the reproduction process.
Despite all this being previously known, there has been no thorough study of the opioid and cannabinoid receptors in the human sperm such as this one, carried out by Mr Ekaitz Agirregoitia Marcos for his PhD thesis, defended at the Faculty of Medicine and Odontology of the University of the Basque Country (UPV/EHU) and entitled in Basque, Opioide-hartzaileak eta kannabinoide-hartzaileak giza espermatozoideetan espresatzen dira eta haien mugikortasunean eragiten dute (Opioid receptors and cannabinoid receptors are expressed in human spermatozoids and influence their mobility).
The aim was to define this expression and the location of three opioid receptors and two cannabinoid receptors, as well as to analyse the influence of their activity in the mobility of spermatozoids. Mr Agirregoitia has a degree in Biology, specialising in Health Sciences. He is currently working as a substitute lecturer in the Department of Physiology, giving classes in Medical Biophysics and General Physiology. His PhD work was led by Dr. Jon Irazusta Astiazaran from the same Department and was undertaken in collaboration with Dr. Carmen Ochoa of the Euskalduna Clinic and Dr. Manolo Guzmán from the Complutense University in Madrid.
Pinpointing the receptors
This PhD has shown, for the first time, that all the types of opioid and cannabinoid receptors are found in human sperm. To date, only the MU opioid receptor has been found in equine sperm, and the presence in human sperm of the CB1 cannabinoid receptor was only discovered this year. Dr. Agirregoitia has used a number of techniques to find three opioid receptors (DELTA, KAPPA and MU) and two cannabinoid receptors (CB1 and CB2) in the human sperm. According to his research, all these are found at the head, the middle and the tail of the spermatozoids.
How is mobility influenced?
After defining the expression and location of the opioid and cannabinoid receptors, Dr. Agirregoitia initiated an analysis of their influence on the mobility of the spermatozoids. These receptors act like a kind of lock catch mechanism to which the opioids and cannabinoids attach themselves. Some of these substances (agonists) are capable of activating the cells, just like a key opening a lock. Others (antagonists), although fitting perfectly into the “locks”, are not capable of opening them and have the effect of blocking the receptor. Mr Agirregoitia studied both processes, incubating human sperm with agonist and antagonist synthetic substances to this end.
From this PhD thesis, presented at the UPV/EHU, it was concluded that, for the movement of the spermatozoids to be maintained, a minimum number of DELTA receptors must remain active. On the other hand, it is pointed out that the activation of the MU opioid receptor inhibits the mobility of the spermatozoids, i.e. it causes them to slow down. Finally, the PhD concludes that the KAPPA opioid receptor participates in another process which has nothing to do with mobility.
As regards the cannabinoid system, the activation of the CB1 y CB2 receptors causes the percentage of spermatozoids with rapid and progressive mobility to be reduced. Even so, as a consequence of the activation of the CB1 receptor, the number of slow spermatozoids rises, while the activation of CB2 increases the number of spermatozoids with progressive but slow movement.
The most effective diagnoses and treatments
It is known that opiods and cannabinoids regulate the function of reproduction through the central nervous system and, according to this PhD thesis, they are also able to control the process through the receptors located in the spermatozoids themselves. Thus, the type and concentration of internal opioids and cannabinoids found in the spermatozoid on its way to the egg will condition its mobility.
This work opens the door – in the medium to long term – to the diagnosis and treatment of numerous pathologies. For example, an analysis of the components of the system of opioid and cannabinoid receptors would enable us to better understand fertility problems due to currently unknown causes, exhibited by both spermatozoids as well as the female reproductive organ. Also, when designing treatment aimed at fomenting the mobility of spermatozoids, it will enable the prescribing of treatment that activates or inhibits the appropriate receptor in order to benefit the process of fertilisation.
https://www.sciencedaily.com/releases/2008/06/080620115953.htm
Researchers Identify Clues About Marijuana Effects
March 9, 2004
Science Daily/Temple University
Scientists have been studying cannabinoids, substances that are chemically related to the ingredients found in marijuana, for more than two decades, hoping to learn more about how the drug produces its effects--both therapeutic and harmful. Marijuana has been reported effective in the treatment of multiple sclerosis, glaucoma, nausea caused by chemotherapy and wasting caused by AIDS. However, like all drugs, it also causes numerous unwanted side effects, including hypothermia, sedation, memory impairment, motor impairment and anxiety. Research on cannabinoids could someday yield new, more effective drugs or drug combinations.
At Temple University's School of Pharmacy and Center for Substance Abuse Research (CSAR), one of only a few centers in the nation focused on the basic science of substance abuse, several researchers are investigating how cannabinoids produce pharmacological effects in rats.
One such study, "L-NAME, a nitric oxide synthase inhibitor, and WIN 55212-2, a cannabinoid agonist, interact to evoke synergistic hypothermia," published in the February issue of the Journal of Pharmacology and Experimental Therapeutics, reveals how cannabinoids produce one of the drug's most robust actions, hypothermia, or decreased body temperature.
According to lead author Scott Rawls, Ph.D., assistant professor of pharmacodynamics at Temple's School of Pharmacy, "To operate at maximum efficiency, the body needs to maintain a stable, normal temperature. When the body's temperature is altered, as in hypothermia, normal body functions, such as blood pressure and circulation, are impaired."
Marijuana operates via two receptors in the body. One receptor, called CB1, is located in the brain and produces the drug's psychoactive effects, including euphoria and dizziness. The other receptor, CB2, is found throughout the body and impacts the immune system. Substances in marijuana bind to one of these receptors and set off a chemical process that leads to an effect, such as hypothermia. Scientists have focused on this chemical process at the molecular level to pinpoint the exact molecules involved.
Knowing that the molecule nitric oxide (NO) plays an important role in the regulation of body temperature, the Temple researchers set out to determine what role it might play in cannabinoid-induced hypothermia. By combining a cannabinoid with a substance that blocked NO synthesis, they found that cannabinoid-induced hypothermia increased more than two-fold.
"This demonstrates the possibility that NO plays a part in regulating the impact of cannabinoids on body temperature and other cannabinoid-mediated actions," said Rawls. "These findings could be helpful in determining the mechanisms that underlie some of the pharmacological actions of marijuana," he added.
Rawls' research team is currently investigating the impact of cannabinoids on other physiological systems, such as analgesia and movement, and the brain neurotransmitters that mediate those systems.
https://www.sciencedaily.com/releases/2004/03/040309071927.htm
Cannabinoids' Role in Retinal Function Described
December 8, 1999
Science Daily/University of California, San Diego
A team led by scientists from the University of California, San Diego (UCSD) has demonstrated the prevalence of cannabinoid receptors in the retina, indicating an important role for cannabinoids—a family of compounds which includes the psychoactive components of marijuana and hashish—in retinal function and perhaps vision in general.
The UCSD researchers, in collaboration with colleagues from The Neurosciences Institute in San Diego and the University of Washington in Seattle, have described for the first time the specific distribution and effects on retinal function of the cellular receptor proteins activated by cannabinoids.
These findings, published in the December 7 issue of the Proceedings of the National Academy of Sciences (PNAS), may provide a missing link in efforts to unravel the complicated and fascinating machinery by which the retina turns light into meaningful information in the brain. The work also provides greater understanding of the effects of marijuana and hashish, drugs which have been used by man for millennia.
“The retina is incredibly complex, highly sensitive to shifts in light levels, and responsive to contrasts, colors and lines,” said Alex Straiker, principal author of the PNAS paper and a graduate student in UCSD's neuroscience program. “We understand very little about how the retina works. By demonstrating that this receptor system is present, we add another piece to the puzzle, opening one more window into how the eye works. It also suggests that marijuana affects vision because it plugs into an existing signaling system that is abundant in the retina.”
Cannabinoids are naturally occurring compounds in vertebrates, and are known to play an important role in intercellular signaling. The chemical THC found in marijuana is a cannabinoid, though different from the ones produced by the body. Two cannabinoid receptors, CB1 and CB2, were discovered only the last ten years. CB1 exists primarily in the central nervous system, while CB2 is found primarily in the peripheral nervous system.
The PNAS paper reports that the retinal cells of rhesus monkeys, chicks, salamanders, goldfish, mice and rats, all similar in many respects to the human eye, contain high levels of CB1. The researchers also found CB1 receptors localized in both rod and cone photoreceptors, the retinal structures that respond to light, processing colors and black and white images. The extensive and consistent localization of these receptors in the retinas of a variety of species suggests that they play a fundamental role in modulating the transmission of signals critical for visual perception.
“The fact that this system is so highly conserved in species separated by hundreds of millions of years of evolution suggests that it's important,” said Straiker. “Nature likes to tinker, so any time you see something this consistent, it raises eyebrows.” The paper also points to a functional role of cannabinoids in the inhibition of calcium channels involved in visual signaling.
“Two key players in the processing of light information in the retina are photoreceptors, which catch light and turn it into a signal that can be interpreted by other cells, and bipolar cells, which are next in line in the flow of information,” said Straiker. “Communication between the cells requires the release of a neurotransmitter called glutamate, triggered by calcium currents passing through a specific calcium channel. Cannabinoids are known to inhibit calcium channels. If you shut down the channel, you shut down the release of glutamate, and profoundly alter the cell's ability to signal.”
Some of the reported effects of the use of marijuana and hashish include the perception of a snowy visual field, increased light intensity and altered vision. In fact, Straiker said his interest in seeking CB1 receptors in the retina was sparked in part by accounts of dramatic alterations in visual perception following marijuana use.
These findings suggest that at least some of the visual effects of marijuana and hashish use occur at the earliest stage of visual processing, as the calcium channels critical for the normal processing of visual information are inhibited.
Co-authors of the paper are Harvey Karten, professor of neurosciences, and Greg Maguire, formerly assistant adjunct professor of ophthalmology, both of the UCSD School of Medicine; Nephi Stella and Daniele Piomelli, formerly at The Neurosciences Institute, and Ken Mackie of the University of Washington.
The research was supported by the National Institutes of Health, The Glaucoma Foundation, and the Neurosciences Institute, which receives major support from Novartis.
Straiker is a graduate student in the UCSD Graduate Program in Neurosciences, ranked as the premier neuroscience graduate program in the country by a National Research Council survey of the National Academy of Sciences. Straiker is presently continuing his work as a graduate student and researcher in the Molecular Neurobiology Laboratory at The Salk Institute, a participating institution.
https://www.sciencedaily.com/releases/1999/12/991208061213.htm