Cannabinoids and Analgesia

Pain pathways are described at three levels: in the periphery, where it originates; at the level of the spinal cord, where some control "gating" the transmission of pain exists; and in the CNS, particularly at the level of the periaqueductal gray. CBj receptors are found on peripheral nerves (59), and injection of anandamide into tissues swollen from carageenan-induced inflammation has been shown to reduce pain in rats (60). But there is much more evidence for a spinal and a central site of action of cannabinoids. To understand better some of the sites and mechanisms of action of cannabinoids, a simplified pain pathway model is presented in Figs. j0 and jj.

5ht Immuno Spinal Cord

Fig. 10. Neurotransmitters and spinal modulation of pain: whereas serotonin (5HT) abolishes pain transmission, y-aminobutyric acid (GABA) increases it by inhibition of the 5HT neuron. Cannabinoids may modulate pain transmission by inhibiting the firing of this GABA neuron, in a way similar to opiates. RVM, rostral ventrolateral medulla.

Fig. 10. Neurotransmitters and spinal modulation of pain: whereas serotonin (5HT) abolishes pain transmission, y-aminobutyric acid (GABA) increases it by inhibition of the 5HT neuron. Cannabinoids may modulate pain transmission by inhibiting the firing of this GABA neuron, in a way similar to opiates. RVM, rostral ventrolateral medulla.

Dopamine Adrenaline Synthesis
Fig. 11. Modulation of pain by descending pathways. Whereas serotonin (5HT) inhibits pain transmission, norepinephrine (NE) stimulates it. An inhibition of NE release through CB, receptors could also explain some of the analgesic effects of cannabinoids.

Pain transmission ascends through the spinal cord to the thalamus and then to somatosensory cortical areas and prefrontal cortex. The main pathway carrying nociceptive stimuli to the brain is the prominent spinothalamic tract. Figure 11 shows that the synapse between the peripheral sensory neuron (first-order neuron) and the secondary projection neuron is under the control of a serotonin-descending neuron, which abolishes the transmission of pain to higher centers. The serotonin neuron is itself under the inhibitory control of a GABA interneuron. When GABA is released, the serotonin neuron is turned off, and pain transmission occurs. Interneurons communicate the ascending information to the reticular formation of the medulla, the periaqueductal gray (PAG) of the midbrain, and the periventricular nucleus of the hypothalamus. These structures in turn modulate pain transmission through descending pathways, synapsing with all the above structures. These pathways have been extensively studied as a site for opiate action and are now relevant as a site of action of cannabinoids as well. For example, the PAG stimulates directly raphe nuclei, where serotonin-containing neurons can inhibit pain transmission (Fig. 12). The PAG also sends signals to the dorsolateral pontomesencephalic tegmentum (DLPMT) and the periventricular nucleus of the hypothalamus. The DLPMT is the beginning of the second major descending pathway, which involves norepinephrine and locus coeruleus neurons. But unlike serotonin, norepinephrine is a nociceptive substance in this modulatory pathway: it causes pain.

Any stimulation of the serotonin-descending pathway, such as through GABA release inhibition, or any inhibition of the noradrenergic-descending pathway, such as through decreased synaptic release of norepinephrine, would result in analgesia.

Evidence shows that THC and cannabinoids prevent pain transmission when injected directly into the spinal cord, the brainstem, or even the thalamus (61). CB1 receptors are very dense in specific layers of the dorsal horn of the spinal cord, where peripheral sensory afferents synapse with second-order neurons to transmit pain to higher centers (62,63). Further, pain itself causes the release of anandamide in the PAG, suggesting that endogenous cannabinoids physiologically play a role in the modulation of pain signaling (64). Because these pathways are generally associated with opiate pharmacology, it was important to investigate if opiate receptors were involved. Results suggest a parallel but distinct neural pathway for cannabinoids and opiates. For example, if morphine and THC were given together, an additive or synergistic effect would be expected. Both rimonabant and naloxone could block this effect, indicating the participation of CB1 and opiate receptors, respectively (65). Opiates are known to decrease GABA release at the level of the serotonergic neuron, resulting in inhibition of an ascending pain pathway. It is possible that cannabinoids may decrease GABA release at the same level, but through a distinct CB1 receptor effect. Some studies suggest an effect on norepinephrine release because intrathecal injection of yohimbine, an a2 antagonist that would increase the synthesis and release of norepi-nephrine at the synaptic cleft, blocks THC-induced analgesia (66). It is interesting to note that CB1 and a2 receptors are negatively coupled to cAMP production through Gi proteins.

CB1 knockout mice bring an interesting development in understanding the complexity of pain modulation by THC and endogenous cannabinoids: anandamide con tinues to cause analgesia in these animals in spite of the absence of CB1 receptor expression, whereas THC does not (67). The discrepancy may be explained by a novel cannabinoid receptor or through anandamide's binding to the vanilloid receptor VR1, which is present in primary afferent sensory neurons (68,69). VR1 is a capsaicin-sen-sitive cationic channel (Na+, Ca2+, K+), and anandamide is proposed to be the endogenous ligand (70). Other stimuli for the channel are heat and protons, and VR1 plays a role in the modulation of intracellular calcium, which in turn regulates neurotransmit-ter release. This new pharmacology is at the center of a debate regarding legalization and the use of Cannabis products in the management of pain as well as in a number of inflammatory disorders.

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  • Maribel
    How does cannabinoids prevent neuronal transmission in pain pathways?
    2 years ago