THE EFFECTS OF ANALGESICS ON NOXIOUS STIMULUS-EVOKED FOS 
EXPRESSION 
Opioids produce their analgesic effects by acting at \i- t 6-, or K-opioid receptors 
(for a review, see Martin 1983) that are located at both supraspinal and spinal 
levels (Basbaum and Fields 1978, 1984). At supraspinal sites, opioids are 
believed to activate neurons in the midbrain periaqueductal gray, which in turn 
excite neurons of the medullary nucleus raphe magnus. The latter neurons 
project to and inhibit spinal cord nociresponsive neurons. Opioids also act at 
opioid receptors in the spinal cord where they can directly inhibit incoming 
nociceptive transmission in the dorsal horn (Yaksh and Noueihed 1985). If 
formalin-evoked Fos immunoreactivity in the spinal cord is, as proposed, 
related to the activity of nociresponsive neurons, then doses of an opioid, 
such as morphine, that produces behavioral analgesia should also inhibit 
noxious stimulus-evoked Fos expression. 
THE EFFECTS OF SYSTEMIC MORPHINE ON FORMALIN-EVOKED FOS 
EXPRESSION 
Presley and colleagues’ (1990) initial studies using systemic morphine injection 
supported the authors’ hypothesis. Systemic administration of morphine, 10 
minutes prior to formalin injection, produced a dose-related inhibition of both 
the pain behaviors and Fos immunoreactivity evoked by the formalin (figure 
5). At the highest dose tested (10 mg/kg, IP), morphine produced a complete 
suppression of the formalin-evoked behaviors and greatly attenuated the levels 
of formalin-evoked Fos immunoreactivity; however, labeled cells could still be 
detected in the superficial dorsal horn. The effects of this dose of morphine 
were reversed by the opiate receptor antagonist, naloxone, consistent with 
activity of morphine at an opiate receptor. The finding that morphine could 
produce complete behavioral analgesia without completely blocking noxious 
stimulus-evoked Fos expression at the level of the cord is important. 
Apparently, analgesia can be achieved without completely “shutting off’’ 
the activity of dorsal horn neurons in the spinal cord. 
As described above, it is important to show not only that the pattern of Fos 
immunoreactivity is stimulus specific but also that the levels of Fos protein in 
the cord are related to the expression of an overt, recordable behavior. In fact, 
the number of Fos-immunoreactive neurons and the magnitude of the animal’s 
behavioral response to formalin are closely related; animals that exhibit the 
highest levels of pain-related behaviors have many Fos-immunoreactive 
neurons in the spinal cord (figure 6). Conversely, animals that are completely 
analgesic exhibit much lower levels of Fos immunoreactivity. This finding 
provides further evidence that Fos expression is a valid measure of neuronal 
activity. 
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