“Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor.
In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn.
Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation.
These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor.
Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.”
https://www.ncbi.nlm.nih.gov/pubmed/11698030
https://www.sciencedirect.com/science/article/pii/S0014299901013097?via%3Dihub
“Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine.
Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa.
As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique.
Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l).
These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.”
“Patients with obesity are susceptible to hypertension and diabetes. Over-activation of 
“Δ9-Tetrahydrocannabinol (Δ9-THC) is the active compound of 
“Cannabis inhalation with a vaporizer may enhance the analgesia of opioids.
In addition, previous research suggest that Cannabis may be useful in attenuating the development of opioid tolerance and dependence.
This is the first human study to show that inhaled cannabis safely potentiates the analgesia of opioids.
“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia and stimulation of brain circuitry that are believed to underlie drug addiction and reward. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs.
The present review addresses the recent advances in the study of biochemical and molecular mechanisms underlying opioid and cannabinoid interaction. Several hypothesis have been formulated to explain this cross-modulation including the release of opioid peptides by cannabinoids or endocannabinoids by opioids and interaction at the level of receptor and/or their signal transduction mechanisms.
Moreover it is important to consider that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception.
Further studies are needed since a better knowledge of the opioid-cannabinoid interaction may lead to exciting therapeutic possibilities.”
“Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems.
Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states.
Indeed, it is widely known that activation of either opioid or cannabinoid systems produce antinociceptive properties in different pain models.
Moreover, several biochemical, molecular and pharmacological studies support the existence of reciprocal interactions between both systems, suggesting a common underlying mechanism.
Further studies have demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception.
These interactions may lead to additive or even synergistic antinociceptive effects, emphasizing their clinical relevance in humans in order to enhance analgesic effects with lower doses and consequently fewer undesirable side effects.
Thus, the present review is focused on bidirectional interactions between opioids and cannabinoids and their potent repercussions on pain modulation.”