[PWT=pain withdrawal threshold... a lower number means greater sensitivity to mechanical pain. Carrageenan was used as the source of mechanical pain here. In A, you see that duloxetine (Cymbalta) restored PWT to normal in both normal mice (WT) and mice without serotonin brain cells (Lmx1b), thus indicating a pain-relieving effect. However, in B at the bottom, fluoxetine (Prozac) did NOT improve the PWT after injection of carrageenan (focus on the black bars), indicating that Prozac does not help this kind of pain in mice without serotonin, meaning that serotonin is an important part of pain regulation, but norepinephrine may be even more important.]
Okay, Dinah, here's something (though it doesn't really "shake things up").
Check out
this article in the Journal of Neuroscience by ZQ Zhao et al., showing pretty good evidence (like we needed more) that the brain neurotransmitter, serotonin (or 5HT), is involved in pain regulation.
What they did was use knockout mice -- mice which have been genetically altered to remove or disable the gene which codes for a given protein -- which have had the codes for serotonin neurons in the brain removed. So, these mice do not have serotonin-producing brain cells. This permits the researchers to see the effect that selective serotonin reuptake inhibitors (SSRIs) and other antidepressants have (or don't have) on the mice.
They were interested in the anti-pain (also called nociceptive) effects of these antidepressants, and the role that serotonin plays. For example, we know that antidepressants which have BOTH serotonin and norepinephrine (NE) effects (SNRIs, like Cymbalta and Effexor) are better at reducing pain than those with solely serotonin effects (SSRIs, like Prozac and Paxil).
So, these particular mice have normal pain responses to hot things, reduced pain responses to mechanical pain (eg, pinch, squeeze, crush... in this study, they simply poked them with different sizes of fishing line), and elevated pain responses to inflammation (eg, an infection, arthritis, etc). The acute analgesic properties of antidepressants were simply nonexistent in these mice. Their acute pain responses were unaffected by antidepressants. However, SNRIs did reduce their responses to chronic pain, while SSRIs did not.
Although the noradrenergic system in Lmx1bf/f/p mice appears to be normal, the analgesic effect of the TCA amitriptyline on acute thermal pain behavior was strongly attenuated in Lmx1bf/f/p mice. Because a total absence of analgesic effect was observed in Lmx1bf/f/p mice treated with fluoxetine and duloxetine, the residual analgesic effect observed in Lmx1bf/f/p mice treated with amitriptyline is likely caused by mechanisms other than blockade of 5-HT and NE reuptake, such as channel modulation and NMDA receptor antagonism (Lawson, 2002; Wang et al., 2004). Together, our data indicate that although the NE component seems to be critical in the analgesic effect of antidepressants, endogenous 5-HT is also of fundamental importance for the analgesic effect of these drugs, especially in reducing thermal sensitivity.
They conclude that "
Together, our data indicate that although the NE component seems to be critical in the analgesic effect of antidepressants, endogenous 5-HT is also of fundamental importance for the analgesic effect of these drugs, especially in reducing thermal sensitivity."
The main reason I posted this is just to demonstrate the cool things one can do with genetics. You can knock out a gene; in this case, the one responsible for turning a developing neuron into a serotonin-producing neuron. You can then figure out what the consequences of that absent gene are. Finally, this also emphasizes how we can learn how to fine-tune our knowledge about pain control, so that more effective -- and less addictive -- treatments can be developed.
