Marijuana and the Cannabinoids

112 Raymon and Walls
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). CB 1
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 CB 1 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 CB 1 receptor effect. Some
studies suggest an effect on norepinephrine release because intrathecal injection of
yohimbine, an α 2 antagonist that would increase the synthesis and release of norepinephrine
at the synaptic cleft, blocks THC-induced analgesia (66). It is interesting to
note that CB 1 and α 2 receptors are negatively coupled to cAMP production through G i
proteins.
CB 1 knockout mice bring an interesting development in understanding the complexity
of pain modulation by THC and endogenous cannabinoids: anandamide con-