Cannabinoids, Acupuncture, TENS, Placebo Effect (Week 3--Melega) Flashcards
Marijuana
Mixture of dried flowering tops and leaves derived from hemp plant, Cannabis sativa L and contains over 400 compounds
Active compounds of cannabis plant are called cannabinoids (>60)
Primary psychoactive constituent is delta-9-tetrahydrocannabinol (delta-9-THC)
Acute effects of cannabis
Produces euphoria and relaxation, perceptual alteration, time distortion and intensification of normal sensory experiences such as eating
Impaired short-term memory and attention, motor skills, reaction time and skilled activities
Feeling of euphoria replaced by anxiety and panic reactions and is common reason for discontinuation of use
Effects on cardiovascular system include tachycardia
Cannabinoids and pain
Cannabinoids can suppress behavioral reactions to noxious stimuli, inflammation and nerve injury
In models of acute or physiological pain, cannabinoids are highly effective against thermal, mechanical and chemical pain
What are the two cannabis receptors?
CB1: expressed mainly in CNS (brain and spinal cord) and reduce Ca2+ influx, inhibit cAMP production
CB2: expressed mainly in immune system and hematopoietic cells
Endogenous ligands for CB (THC/cannabis) receptors
Derivatives of arachidonic acid
Anandamide and 2-arachidonyl glycerol both bind CB1 receptor and produce pharmacological effects similar to THC and synthetic derivatives
Mechanisms of action include postsynaptic release of endcannabinoids that activate presynaptic CB1 receptors
Endogenous system for pain and pleasure that is significantly modulated through cannabinoid neurotransmission
Approved prescription drugs that are synthetic molecules with higher selectivity, metabolic stability, and efficacy than THC
Dronabinol (Marinol): capsules of THC in sesame oil
Nabilone (Cesamet): synthetic THC analog
These drugs prescribed for: appetite stimulation, nausea and vomoting following anticancer therapy, analgesia (desensitizing nociceptive neurotransmission), glaucoma (may lower IOP)
How do cannabinoids reduce pain responses (analgesics)?
Cannabinoids reduce pain responses in a range of nociceptive and neuropathic pain models
Cannabinoid receptor-mediated analgesic actions operate at sites concerned with transmission and processing of nociceptive signals in brain, spinal cord and periphery
Potentially modulate functions of neuron and immune cells that mediate nociceptive and inflammatory responses
Precise signaling mechanisms unclear
Are cannabinoids clinically effective as analgesics?
Unclear
Need cannabinoids with a more favorable therapeutic index than those currently available for human use, and need to test efficacy and side-effects in high-quality clinical trials
Endocannabinoid system of the brain
1) Endocannabonoids (AEA and 2-AG) synthesized IN POSTSYNAPTIC MEMBRANE on demand following depolarization of postsynaptic membrane
2) Diffuse (“backwards”) into synaptic cleft and bind presynaptically localized CB1 receptors
3) This causes inhibition of NT (glutamate or GABA) release due to reductions in Ca2+ and increases in K+
4) Endocannabinoid signaling terminated by cellular uptake processes (likely involve transporter proteins)
Effects of endogenous cannabinoid system
Short term: inhibition of glutamate or GABA release
Long term: endocannabinoids modulate protein kinases and gene transcription
Note: any drug that gets to the brain will cause some sort of change in the brain
What might contribute to the reinforcing and abuse properties of marijuana?
Marijuana increases activity of dopaminergic neurons in ventral tegmental area–mesolimbic pathway
Dopaminergic circuits known to play a pivotal role in mediating reinforcing (rewarding) effects of most drugs of abuse, so enhanced dopaminergic drive elicited by cannabinoids might underlie reinforcing and abuse properties of marijuana
(same common neuronal action with other major drugs of abuse (morphine, ethanol, nicotine) which facilitate mesolimbic dopamine system)
Cannabinoids and glaucoma
Lower IOP and have neuroprotective actions
CB1 receptors in ciliary epithelium, trabecular meshwork, Schlemm’s canal, ciliary muscle, ciliary body vessels, retina
Cannabinoids could influence endogenous cannabinoinds on trabecular and uveoscleral AH outflow and AH production
However, no need for cannabinoid drug because glaucoma drugs (lantanaprost, timolol) so effective already
Placebo effect
Effect that follows the administration of an inert treatment (the placebo)
In context of pharmacology: beneficial effect of treatment or drug that is thought to not be specific to the drug but rather to unspecific circumstances of the treatment
Note: nocebo response is worsening of symptoms due to unspecific factors
What could “unspecific” treatment effects be?
Predisposing individual factors from the physician (training, empathy, suggestions)
Predisposing individual factors from the patient (worries and concerns, previous illness experience and a history of successful or failed therapy)
Generally the placebo response depends on patient’s belief or expectation that the therapy is effective
Is the placebo the inert substance alone?
No, it is the administration within a set of sensory and social stimuli that tell the patient that a beneficial treatment is being given
Effect is because of psychosocial context that surrounds the inert substance and the patient
Three phenomena that cannot be distinguished as causative of change in placebo clinical trials
True placebo responses: real psychobiological phenomenon; mind activating endogenous neurochemical pathways
Natural history: spontaneous remission of symptom which can occur regardless of any treatment being administered
Phenomenon of regression to the mean: statistical phenomenon whereby a measurement in a clinical trial tends to be higher at a first evaluation compared with a second assessment
Acupuncture
Inserting one or more needles into specific sites on body surface for therapeutic purposes
Two strategies: (1) manual acupuncture and (2) electroacupuncture
(TENS is related)
Theories as to how acupuncture causes analgesia and other clinical effects
1) Stimulation of A delta fibers in skin and muscle conduct impulses to spinal grey matter and inhibit painful stimuli from periphery and reduce pain perception
2) Activate enkephalin-containing interneurons in substantia gelatinosa of spinal cord/dorsal horn resulting in inhibition of conduction of pain signals to brain
3) Release of beta-endorphin and met-enkephalin in the brain; effects blocked by naloxone
4) Activation of 2 descending pain control systems in midbrain
5) Modulatory effects on central pain network in the hypothalamus and limbic system
What can and can’t acupuncture be useful for?
Effective: dental pain, fibromyalgia, nausea/vomiting, knee OA, insomnia, chronic back pain, idiopathic headache
Not effective: addiction, insomnia, obesity, asthma, stroke deficits
Transcutaneous electrical nerve stimulation (TENS)
Commonly used form of electroanalgesia
Used for low back pain, myofascial and arthritic pain, sympathetically mediated pain, bladder incontinence, neurogenic pain, visceral pain, postsurgical pain
Proposed mechanism of neuromoduation: presynaptic inhibition in dorsal horn of spinal cord; endogenous pain control via endorphins, enkephaline, dynorphins; direct inhibition of abnormally excited nerve
Analgesia produced by TENS and gate control theory
Gate is usually closed, inhibiting constant nociceptive transmission via C fibers from periphery to dorsal horn
When painful peripheral stimulation occurs, the info carried by C fibers reaches dorsal horn and opens gate, allowing pain transmission centrally to thalamus and cortex, where it is interpreted as pain
Gate-control theory postulates a mechanism by which gate is closed again, preventing further central transmission of nociceptive info to the cortex
Proposed mechanism of TENS for closing the gate is inhibition of C-fiber nociception by impulses activated in different, myelinated fibers
