Other receptors to which cannabinoids bind

Cannabinoids bind not only to the classic cannabinoid receptors (see above), but also to other receptors.

• 1. TRPV1
• 2. PPARα (Peroxisome Proliferator-Activated Receptor alpha)
  • 2.1. Control ranges of PPARα
  • 2.2. What influences PPARα
  • 2.3. Involvement of PPARα in disorders
  • 2.4. Agonists and antagonists of PPARα
• 3. PPARγ (Peroxisome Proliferator-Activated Receptor gamma)
• 4. GPR55
• 5. GPR119
• 6. More GPR

1. TRPV1¶

Some cannabinoids also bind to TRPV1 (transient receptor potential cation channel subfamily V member 1, transient receptor potential cation channel of subfamily V (for vanilloid), subtype 1, obsolete vanilloid receptor 1 (VR1) or capsaicin receptor). TRPV1 was first described in 1997.¹
TRPV1 is primarily a peripheral pain receptor. It reacts to various environmental factors and agonists, which is why all these stimuli feel comparable (burning sharpness as well as burning from heat or burning from acid).
TRPV1 is a polymodal ion channel. TRPV1 is activated by various physical or chemical stimuli:²

• Flavor sharpness
• Temperatures from 42 degrees
• pH value below 5.9
• Tension
• mechanical force
• Agonists
  • Capsaicin (paprika and chili peppers)
  • Various toxins³⁴
    • Psalmotoxins
    • Vanillotoxins (tarantula, Psalmopoeus cambridgei)
    • DkTx
    • RhTx
    • BmP01
    • Echis coloratus Toxins
    • APHCs
    • HCRG21
    • Botulinum neurotoxin
    • Resiniferatoxin (spurge family)⁵
    • Scorpion venom
    • Spider toxin
    • Ciguatera fish poisoning (CFP)
    • neurotoxic shellfish poisoning (NSP)
    • Latoia consocia caterpillar venom⁶

In the brain, TRPV1 has no role in pain perception.
In the following, we present the effects and interactions of dopamine in particular.

TRPV1 is found on dopaminergic neurons in the VTA, especially during birth.
TRPV1 mediates various dopaminergic-influenced effects:

• TRPV1 influenced the sensitivity to amphetamine.⁷
• Striatal TRPV1 activation by paracetamol improves orofacial dyskinesia induced by D2 receptor antagonists.⁸
• TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease through TRPV1-mediated endogenous production of ciliary neurotrophic factor (CNTF)⁹

TRPV1 is found in the brain at sites that are not necessarily activated by classic inflammatory processes due to the blood-brain barrier¹⁰, such as:¹¹

• Nucleus tractus solitarius
• Area postrema
• Locus coeruleus
• preoptic area of the hypothalamus
• many cortical regions
  • e.g. in pyramidal neurons¹²
• limbic system
  • Hippocampus
    • especially on pyramidal neurons¹²
  • central amygdala
  • medial and lateral habenula
• Substantia nigra
• Cerebellum
• Thalamus nuclei
• inferior olive
• Olfactory bulb⁵
• Striatum⁵
  • in fibers and postsynaptic¹³
• Mesencephalon⁵
• periaqueductal gray⁵
• Hindbrain¹²

TRPV1 can be found in¹²

• Synapses (predominantly, but not exclusively in postsynaptic dendritic spines)
  • pre- and postsynaptic.¹⁴
• at the end feet of astrocytes
• in pericytes
• in neurons

Endogenous TRPV1 agonists are:¹⁵

• 9(10)-EpOME (9(10)-epoxy-12Z-octadecenoic acid, epoxy metabolite of linoleic acid)
• 9, 10-DiHOME (9,10-dihydroxy-12Z-octadecenoic acid, hydroxy metabolite of linoleic acid)
• 9-HODE (9-hydroxy-10E,12Z-octadecadienoic acid, hydroxy metabolite of linoleic acid)
• 9-oxoODE (9-oxo-10E,12Z-octadecadienoic acid, epoxy metabolite of linoleic acid)
• 12(13)-EpOME (12(13)-epoxy-9Z-octadecenoic acid, epoxy metabolite of linoleic acid)
• 12(S)-HPETE (12(S)-hydroperoxyeicosatetraenoic acid)
• 12, 13-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid)
• 12/15 -LOX (12/15-Lipoxygenase)
• 13-HODE (13-hydroxy-9Z, 11E-octadecadienoic acid, LA derivative)
• 13-oxoODE (13-oxo-9Z,11E-octadecadienoic acid)
• 20-HEPE (20-hydroxyeicosapentaenoic acid, derived from EPA)
• 20-HETE (20-hydroxyeicosatetraenoic acid, derived from AA)
• 22-HDoHE (22-hydroxydocosahexaenoic acid, derived from DHA)
• α-Linolenic acid (ALA)
• Anandamide (AEA)
• Arachidonic acid (AA)
• Cyclooxygenase-1,-2 (COX-1,-2)
• Cytochrome P450 (CYP450)
• Docosahexaenoic acid (DHA)
• Eicosapentaenoic acid (EPA)
• Epoxyeicosatrienoic acids (EETs)
• Hepoxilin A3 (HXA3)
• Hepoxilin B3 (HXB3)
• Hydroxyeicosatetraenoic acids (HETEs)
• Leukotriene B4 (LTB4)¹⁶
• Linoleic acid (LA)
• Epidermal type 3 lipoxygenase (eLOX-3)
• Lysophosphatidic acid (LPA)
• Polyunsaturated fatty acids (PUFAs)
• N-acylamino acids/neurotransmitters (NAANs)
• N-acylethanolamines (NAEs)
• N-acylphosphatidylethanolamines (NAPEs)
• N-arachidonoyl dopamine (NADA)¹⁶
• N-arachidonoyl-GABA (A-GABA)
• Sodium hydrogen sulfide (NaHS)
• N-docosahexaenoyl GABA (D-GABA)
• N-Linoleoyl-GABA (L-GABA)
• Oleoyl ethanolamine (OEA or NOE)
• Oxytocin
• Palmitoylethanolamide (PEA)
• Hydrogen sulphide (H2S)

Exogenous TRPV1 agonists:

• Alcohol¹⁷
• AM404
  • FAAH inhibitors also appear to act as TRPV1 agonists.¹⁸
• Arvanil (AR) synthetic “hybrid” agonist of CB1R and TRPV1¹⁹
• Capsaicin (CP)¹⁹
• CBD (activation/desensitization)
  • TRPV1 agonist
    • possibly antipsychotic effect²⁰
  • TRPA1 (ankyrin type 1; activation/desensitization)
  • TRPV2 (vanilloid type 2; activation/desensitization)
  • TRPM8 (melastatin type 8; inhibition)
• D3, vitamin D²¹
  • Partial agonist
• Caffeine (1,3,7-trimethylxanthine)²²¹⁷
  • TRPV1 agonist²³
  • TRPA1 agonist in rodents²³
  • TRPA1 antagonist in humans²³
• Olvanil (OL)¹⁹
  • Capsaicin derivative

TRPV1 antagonists:

• Capsazepine
  • blocked the pain-relieving effect of CBD²⁴
  • competitive antagonist for capsaicin and resiniferatoxin⁵
• (E)-CBG (cannabigerol)²⁵²⁶
  • weak TRPV1 and TRPV2 agonist
• Iodo-Rsiniferatoxin⁵
  • competitive antagonist
• Ruthenium red⁵

Dopamine modulates TRPV1²⁷

• D1/D5 agonists inhibited capsaicin-induced TRPV1 signaling
• a D2 agonist did not alter TRPV1 signaling

2. PPARα (Peroxisome Proliferator-Activated Receptor alpha)¶

Three human isoforms of PPAR are known: PPAR-α (alpha), PPAR-β/δ (beta or delta) and PPAR-γ (gamma). Other names are NR1C1, NR1C2 and NR1C3.²⁸

Occurrence of PPARα:²⁹³⁰
PPARs are located inside cells. Ligands must therefore first be taken up by the cell.³¹

• PFC
  • PPARα (and PPARγ) are found on 70% of midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice³²
• Basal ganglia
• Nucleus accumbens
  • PPARα (and PPARγ) are not found on GABA neurons in the nucleus accumbens³²
• Amygdala
  • PPARα is found on ~60% of glutamatergic neurons³²
  • PPARγ is found on ~60 % of the GABA neurons³²
• VTA
• Thalamus nuclei
• Hippocampus (lower)
  • in CA1, CA2, CA3 and dentate gyrus

2.1. Control ranges of PPARα¶

Control ranges of PPARα are among others:²⁹³⁰

• Modulation of VTA and amygdala
  • PPARα agonists reduce the activity of dopamine cells as well as the net output of the VTA through negative modulation of beta2-nAChR³³
  • PPARα agonists reduce the number of spontaneously active dopamine neurons³³
• Reward
  • Mice that can trigger optogenetic stimulation of DA neurons in the midbrain themselves³⁴ perceive this as rewarding³²
  • THC and a PPARγ agonist (but not a PPARα agonist) inhibited self-stimulation in a dose-dependent manner³²
  • A PPARγ agonist increased locomotion in the open field (sign of reduced anxiety), PPARα or PPARγ antagonists reduced it³²
• Motivation
• Mood disorders, anhedonia, depression (see below for details)
• Regulation of peroxisomes³⁵
• Regulation of mitochondrial β-oxidation³⁵
• Thermogenesis³⁵
• Lipoprotein metabolism³⁵
  • PPARα agonists change the fatty acid profile³⁶
  • PPARα is a transcription factor for several enzymes involved in fatty acid metabolism³⁶
• Energy homeostasis³⁷
  • PPARα agonists increase glucose metabolism³⁵
• PPARα agonists cause insulin sensitization³⁵
• PPARα activation increases PEA and OEA levels, which can further maintain PPARα activity as PEA and OEA are PPARα agonists³⁶
• Neuroinflammation³⁷
• Proliferation/differentiation of glial cells³⁷
• antioxidant reactions³⁷
• Neurogenesis³⁷
  • PPARα agonists increase BDNF and other neurotrophic factors³⁸
• Neurotransmission³⁷
• dopaminergic activity in terminal regions of the VTA
  • acute or chronic stimulation of PPARα influences β2nAChRs in dopaminergic neurons in the VTA³³³⁹
  • β2nAChR regulates firing rate of dopaminergic neurons in the VTA⁴⁰
  • chronic administration of the synthetic PPARα agonist fenofibrate⁴¹
    • reduces the phosphorylation of β2nAChRs
    • resulting in increased phasic firing of VTA dopamine neurons
    • alleviated depressive symptoms
    • restored dopaminergic response to relevant stimuli in the nucleus accumbens
• Orchestration and modulation of stress reactions⁴²
  • by means of increased biosynthesis of neurosteroids and allopregnanolone/pregnanolone⁴³
• fewer side effects than selective PPARγ agonists, which are only of limited use due to side effects such as weight gain, heart failure, bone fractures, macular edema and peripheral edema⁴⁴

2.2. What influences PPARα¶

PPARα is influenced by:

• Stress²⁹
  • various chronic stress protocols that induce depression symptoms in rodents. (social defeat, unavoidable stress and social isolation) significantly reduce PPARα expression in the hippocampus, but not in the mPFC, nucleus accumbens or VTA
  • induced epigenetic PPARα downregulation with hypermethylation of the promoter region
  • a single dose of the PPARα agonist PEA caused stress-induced depression and PTSD in the socially isolated mouse, an animal model for prolonged stress-induced depression and PTSD:^43454647
    • Allopregnanolone increased in PFC, amygdala, hippocampus and olfactory bulb
    • aggressive behavior attenuated
    • Depression symptoms reduced
    • Reduced anxiety symptoms
• Low methionine diet⁴⁸

2.3. Involvement of PPARα in disorders¶

PPARα is involved in various disorders:²⁹

• Depression⁴³⁴⁹
  • downregulated PPARα expression in the hippocampus increased depression symptoms in mice³⁸
  • PPARα overexpression in the hippocampus had an antidepressant effect in mice³⁸⁵⁰
  • PPARα agonists have an antidepressant effect²⁹
    • PEA has an antidepressant effect in mice⁵¹ and rats⁵²
    • Fenofibrate has an antidepressant effect⁴¹
      • also via BDNF in the hippocampus⁵³
    • Gemfibrozil has an antidepressant effect⁵⁴
    • Quercetin has an antidepressant and estrogen-like effect⁵⁵
  • Fluoxetine (SSRI) ³⁸, venlafaxine (SNRI)⁵⁶ and reboxetine (NRI) ⁵⁷ are (also) dependent on PPARα for their antidepressant effect
• ASS
  • PPARα agonists improved autistic symptoms⁵⁸
    • PEA in humans⁵⁹, in mice⁶⁰ and rats⁶¹
    • Fenofibrate (selective agonist)⁶²⁶³
  • pPARγ agonists also improved autistic symptoms in mice:
    • Pioglitazone (selective agonist)⁶⁴⁶⁵
    • Diosgenin (selective agonist)⁶⁶
  • PPARγ agonists proved to be protective against ASA⁶⁷
    • Pioglitazone⁶⁸
  • autistic behavioral deficits correlate with reduced PPARα expression levels in PFC and hippocampus in animal models
    • repetitive behavior⁶⁹
    • Behavioral rigidity⁶⁹
• Huntington⁷⁰
• Multiple sclerosis^71727374
• Parkinson’s disease⁷¹³⁶
• Alzheimer’s disease⁷¹⁷⁵⁷⁶
• Neuropathic pain⁷¹
• Nicotine addiction
  • PPARα agonists are discussed as active ingredients against (nicotine) addiction⁷⁷⁷⁸³⁶
  • PPARα agonists reduce the increased locomotion triggered by nicotine³³
• PTSD
  • reduced hair and blood levels of various PPARα agonists^{7980 81 44}
• ADHD: no positive effect known to date
  • A common denominator of all neuropsychiatric disorders, including schizophrenia and ADHD, is an increased inflammatory response of the brain, which can arise in a variety of ways:⁸²
    • Exposure to pro-inflammatory substances during development
    • Accumulation of degenerated neurons, oxidized proteins, glycated products or lipid peroxidation in the adult brain
  • against the background of the anti-inflammatory effect of PPARα agonists and the activating effect on phasic dopamine in the VTA described above, we do not rule out a helpful contribution of PPARα agonists in ADHD

2.4. Agonists and antagonists of PPARα¶

Endogenous agonists:

• polyunsaturated fatty acids²⁹
  • Arachidonic acid³¹
• saturated fatty acids²⁹
• Eicosanoids²⁹
  • 8-Hydroxyeicosatetraenoic acid⁸³
• Leukotrienes²⁹
  • LTB4⁸⁴
• oxidized fatty acids²⁹
• oxidized phospholipids²⁹
• Polyphenols⁸³
  • Resveratrol⁸³
• Fatty acid ethanolamides²⁹
  • Anandamide (AEA, arachidonoylethanolamide⁸⁵ (partial agonist)⁸⁶
  • PEA (palmitoylethanolamide)⁸⁷
    • Binding affinity in the nanomolar range (= low Kd = high binding)²⁹
  • OEA (oleoylethanolamide)⁸⁸
    • Binding affinity in the nanomolar range (= low Kd = high binding)²⁹
• Oleamide ((Z)-octadec-9-enamide)⁸⁹

Exogenous agonists:

• CBD
• CBDA (cannabidiolic acid)
  • PPAR-α and PPAR-γ agonist⁹⁰
• (E)-CBG (cannabigerol)
  • PPAR-α and PPAR-γ agonist⁹⁰
    Fibrates
  • Fenofibrate²⁹
  • Gemfibrozil²⁹
  • Bezafibrate³¹
  • Ciprofibrate⁸³
• GW7647²⁹
• WY-14643²⁹
• synthetic piperidine agonists
  • CP-865529
  • CP-775146
  • CP-868388

Agonists by binding strength Kd in nanoMolar (nM) (low Kd = high binding):⁸⁴ Nanomolar = high binding, micromolar (mM) = low binding.

• Bezafibroyl-CoA thioester: 2.7 nM

• Linoleic acid: 4.8 nM

• Oleic acid: 5.9 nM

• Linolenic acid: 7.9 nM

• CP-868388: 10.8 nM (Ki)

• Wy14643: 11.06 nM (Ki)i⁸³

• Bezafibrate: 13.1 nM

• Arachidonic acid: 17.3 nM

• CP-775146: 24.5 nM (Ki)

• WY14643: 28.8 nM

• Parinaric acid: 30.0 nM

• Leukotriene LTB4: 60.8 nM

• CP-865529: 74 nM (Ki)

• 8-Hydroxyeicosatetraenoic acid: 100 nM⁸³

• PEA (palmitoylethanolamide): probably nanomolar; Kd unknown, EC50 value: 3.1 ± 0.4 µM

• OEA (oleoylethanolamide): nanomolar

• Stearic acid: weak

• Fenofibrate 10-20 μM / mM⁸³

3. PPARγ (Peroxisome Proliferator-Activated Receptor gamma)¶

It is possible that PPARγ agonists could help to normalize the chronobiorhythm that is shifted in ADHD.
In vitro, the PPARγ agonist rosiglitazone significantly equalized the chronobiological patterns in cultured human skin fibroblasts from persons with ADHD and control groups by causing phase shifts in the expression of the clock genes BMAL1, PER3 and CRY1. The amplitude and phase of CLOCK1, NPAS2 and PER1 were only slightly altered, while the gene expression of PER2 and PER3 was not changed at all.⁹¹

4. GPR55¶

GPR55 has been associated with various physiopathological conditions, such as⁹²

• motor coordination
• Pain
• Metabolic disorders
• Vascular functions
• Bone physiology
• Cancer

Agonist:

• PEA (palmitoylethanolamide)²⁹
• LPI (lysophosphatidylinositol)⁹²
• THC (probably binds without activating effect)⁹²

Antagonist:

• CID16020046⁹³

5. GPR119¶

GPR-119 is mainly expressed in the pancreas and the gastrointestinal tract⁹⁴
GPR-119 serves as a glucose-dependent insulinotropic receptor⁹⁵
GPR-119 is coupled to Gαs in the insulin-producing islet cells of the pancreas⁹⁵

Agonist:

• OEA (oleoylethanolamide)⁹⁶

6. More GPR¶

Other receptors associated with the cannabinoid system were discussed⁹²

• GPR 3
• GPR 6
• GPR12
• GPR18
  • Lymphatic tissue (frequent)
  • Brain (moderate)
  • Lungs (moderate)
  • Testicles (moderate)
  • Ovaries (moderate)
  • Agonists:
    • NAGly (N-arachidonoyl glycine)
    • RvD2 (Resolvin D2)