Cannabinoid Mechanisms of Pain Suppression 511to discussing how cannabinoids and endocannabinoids modulate pain sensation.
Extensive reviews of pain mechanisms may be found in a relatively recent volume
edited by Wall and Melzack (1999). This review will focus on preclinical studies
that evaluate evidence from neuroanatomical, behavioral, electrophysiological,
and neurochemical approaches that provide insight into the roles of cannabinoids
and endocannabinoids in suppressing pain. Peripheral, spinal, and supraspinal
sites of cannabinoid actions are discussed, as well as the endogenous ligands
implicated in endocannabinoid mechanisms of pain suppression. This review will
also present results from clinical studies that provide insight into the therapeutic
potential for cannabinoid pharmacotherapies for pain in man.
1
Brief Overview of Pain Mechanisms
Pain is a complex psychological phenomenon comprising sensory, emotional, and
motivationalcomponents.Thenegativeemotionandthemotivationtoescapefrom
the stimulus are essential features of pain—without them the experience would be
non-painful tactile stimulation. In the early twentieth century, “labeled-line” the-
ory dominated thinking about pain. In this conception, specific nociceptors in the
periphery transmit signals about noxious stimuli to the spinal cord, which relays
the information to a pain center in the brain, which in turn gives rise to the sensa-
tion of pain. This notion has broken down, first with the realization that while there
are specific nociceptors in the periphery, activity from incoming non-nociceptive
fibers interacts with that from nociceptors, changing the spinal transmission prop-
erties of the nociceptive fibers. Hence, increased activity in larger, non-nociceptive
fibers lessens the impact of activity in nociceptors (typically smaller unmyelinated
C fibers and finely myelinated Aδfibers). The second and perhaps even more sig-
nificant finding was the discovery that the brain contains circuits that modulate the
ability of nociceptors to excite ascending pain-transmission pathways. These cir-
cuits can either dampen or facilitate pain. The observations by Beecher (1959), who
observed soldiers in World War II who felt no pain despite serious injuries, were
important in rethinking the labeled line theory, leading to the more sophisticated
view that the experience of pain is regulated by the relative activity in peripheral,
spinal, and brain networks of pro- and anti-nociceptive circuits. These networks,
describedinmoredetailbelow,providesubstratesforactionsofcannabinoidson
pain.
1.1
Nociceptors
The term nociceptor refers to sensory receptors that respond to noxious stimuli
(see Kruger et al. 2003 for review). A variety of cutaneous primary afferent nocicep-
tors have been described, primary among them are the unmyelinated C fibers that
are characterized by free nerve endings. The C-polymodal nociceptor responds to