The opioid system plays a critical role in both the experience and management of pain. While acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in chronic pain patients, but are unable to (i) determine if these changes are due to the chronic pain itself or to pre-existing or medication-induced differences in the endogenous opioid system, and (ii) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [18F]-FDPN-PET in either sham rats (n=17) or spared nerve injury rats (SNI; n=17), we confirmed reduced opioid receptor availability in insula, caudate-putamen and motor cortex of nerve injured rats three-months post-surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in caudate-putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate-putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human chronic pain patients may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.
aDivision of Intramural Research, National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland; 35A Convent Drive (room 1E-450), Bethesda, Maryland, 20892 USA.
bDivision of Intramural Research, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; 10 Center Drive (room B2C315), Bethesda, Maryland, 20814 USA.
cFaculty of Dentistry, McGill University, Montreal, QC, Canada; 740 Dr. Penfield Avenue (Suite 3200), Montreal, QC H3A 0G1.
Corresponding author: Mark H. Pitcher, Ph.D. National Center for Complementary and Integrative Health National Institutes of Health 35A Convent Drive, RM. 1E420 Bethesda, MD 20892 Email: email@example.com
Conflict of interest: The authors declare no competing financial interests.