We provide the first direct evidence of short- and long-term effects of acupuncture therapy on central MOR binding availability in chronic pain patients. Overall we find that traditional acupuncture therapy evokes an increase in MOR availability over both short and long periods. These changes were absent in sham treated patients where either no change was detected or decreases in MOR BP were observed. Reduction in central MOR BP during SA is consistent with increased endogenous opioid release during placebo administration (Zubieta et al., 2005
; Scott et al., 2008
). For both short- and long-term effects of TA, areas showing increases in BP included a number of brain regions classically implicated in the regulation of pain and stress in humans (Zubieta et al., 2001
; Zubieta et al., 2003b
), such as the amygdala, the dorsal and perigenual anterior cingulate, and the insular cortex. Other regions also shown to be involved in responses to pain and other salient stimuli and where TA induced significant effects on MOR BP included the nucleus accumbens, the caudate, and the putamen (Gear and Levine, 1995
; Scott et al., 2006
). The nucleus accumbens and the dorsal cingulate are both regions that we identified previously as showing reduced binding in FM patients as compared to controls (Harris et al., 2007
). Finally, a region of the temporal pole showed increases in binding following TA for both short and long time periods, and displayed a significant negative correlation with changes in clinical pain. This temporal pole region has previously been identified as showing responsiveness to negative mood (Kennedy et al., 2006
; Zubieta et al., 2003b
) as well as acupuncture treatment (Napadow et al., 2005
; Hui et al., 2000
Our findings of widespread increases in regional MOR binding availability are consistent with a previous trial of acupuncture in rodents showing that acupuncture induces an increase in the number of central MOR binding sites following treatment (Gao et al., 1997
). For changes that arise following long-term therapy, this could involve increased transcription and translation of MORs and their subsequent insertion into the plasma membrane. Indeed acupuncture treatment has been shown to modulate the levels of transcription factors within the central nervous system (Lao et al., 2004
). However this explanation does not address the relatively rapid increases in MOR BP that we observe (i.e. within 45 minutes) following needle insertion. One possible explanation originates from animal and tissue preparations where increases in the plasma membrane expression of all three classes of opioid receptors have been shown occur in neurons following excitation. The sub-cellular localization of μ- (Browning et al., 2004
), κ-(Shuster et al., 1999
), and Δ- (Bao et al., 2003
) opioid receptors all appear to be dynamically regulated by neural activity. Following neuronal excitation, all three classes of receptors have been shown to be trafficked to the plasma membrane within the time frame that we observe our short-term acupuncture effects (i.e. within 45 minutes). This type of regulation of glutamate receptors has been observed during long-term potentiation (LTP) and long-term depression (LTD) where neuronal activity modulates receptor expression at the plasma membrane (Malenka, 2003
). Interestingly a recent study by Xing et al. suggests that acupuncture can also induce LTD in the spinal cord in a rat model of chronic pain and this depression is abolished by the opioid receptor antagonist naloxone (Xing et al., 2007
). LTD-type modulation of MORs and subsequent changes in synaptic strength could function as a mechanism for acupuncture analgesia given the lasting effects of acupuncture observed here and in other clinical trials (Brinkhaus et al., 2006
; Linde et al., 2005
; Melchart et al., 2005
; Witt et al., 2005
Another intriguing result from the present study is that although MOR BP values were differentially altered by TA and SA, reduction in clinical pain was similar between groups. In a clinical trial, when an active treatment does not exhibit superior efficacy to a sham or placebo, the active treatment is assumed to be ineffective and only operating via a placebo effect. However this study suggests that this may be an erroneous conclusion. In this instance, our non-insertion sham procedure evoked a similar reduction in pain as our true acupuncture and we speculate that this occurred via a different mechanism. The analgesic effects of SA could have been due to regional reductions in MOR BP, consistent with activation of this class of receptors during placebo effects (Zubieta et al., 2005
), whereas TA evoked an increase in receptor binding availability. This interpretation is entirely consistent with the observed positive correlation between decreases in MOR BP within the dorsolateral prefrontal cortex and decreased pain in the SA group. These reductions in MOR BP may also be operating in TA however these effects may be “masked” by the increases in receptor binding availability noted above.
Finally we explored the relationship between increases in MOR BP following acupuncture and subsequent changes in clinical pain. We found that many of the same regions showing increases in binding following acupuncture therapy were also associated with reductions in clinical pain. Since our previous study found reductions in MOR BP in FM patients (Harris et al., 2007
), acupuncture may act to increase or “normalize” MOR binding ability in FM patients to levels that are more representative of pain free controls.
To determine if participants could tell the difference in treatments and unblind the trial, we asked our participants to guess which treatment they thought they received following the first PET imaging session. We found that both groups had similar guesses for their treatment assignments suggesting our results were not likely to be explained by participant knowledge of treatment assignment.
In this work some participants were taking medications, however we monitored closely their usage (see Supplementary Table 2
). Patients remained on stable doses of existing medications for the entire duration of the study. Therefore, medications are unlikely to represent a confounding factor in the analyses presented. Any medication confound would be operative in both pre- and post-treatment scans as well as for TA and SA groups.
Our sham intervention was performed on non-acupuncture points and did not involve skin penetration. Therefore our differential effects of TA and SA may be due to point location and/or skin penetration. Future studies are needed to determine if the differential effects on MOR BP are due to either skin penetration or acupuncture point stimulation or a combination of both.
Overall our data strongly imply divergent opioid receptor mechanisms in acupuncture and sham acupuncture therapy. Although the fundamental mechanisms underlying these processes await further investigation, central opioid receptors appear to be involved in both treatments, albeit with differing effects within the same brain structures. Greater insight into these effects may be obtained in animal models of chronic pain disorders.