When citing an abstract from the 2009 Annual - Society for ...

Topic: D.08.bb. Opioids
Support: NIDCR Grant R01 DE16558
NINDS U01-DE017018
P01 NSO45685
Title: The role of MOR-1K in opioid induced hyperalgesia
Authors: *M. S. CONRAD, S. WENTWORTH, D. PRUSIK, J. GAUTHIER, R. SUKUMAR,
W. MAIXNER, L. DIATCHENKO, A. NACKLEY;
Ctr. for Neurosensory Disorders. Sch. of Dent., UNC-CH, Chapel Hill, NC
Abstract: Opioids have become one of the most widely used drugs in chronic pain treatment
despite many side effects including dependence, addiction, and withdrawal. A substantial
proportion of chronic opioid users also experience an increase in pain sensitivity termed opioid
induced hyperalgesia (OIH). The majority of prescribed opioids, including the most broadly used
opioid, morphine, mediate physiological effects through binding to the mu opioid receptor MOR-
1. MOR-1 is a seven transmembrane G-protein-coupled receptor whose analgesic function is
facilitated through the cellular inhibition and subsequent hyperpolarization of the cellular
membranes. Recently, our group identified a novel isoform of MOR-1, MOR-1K, which codes
for a truncated six transmembrane receptor. The minor allele T of the rs563649 polymorphism
carried by the MOR-1K isoform is associated with both increased pain sensitivity and decreased
analgesic efficacy of morphine in humans, though it codes for higher translation efficiency of the
receptor. Preliminary characterization of this isoform has shown it to have an excitatory cellular
function mediated by increased cAMP, Ca 2+ , and NO production opposite to inhibitory cellular
effects of the major MOR-1 isoform. We hypothesize that MOR-1K plays a pivotal role in the
development of OIH through this excitatory cellular function. For this study, we utilized three
strains of mice which exhibit different responses to morphine. Mice received subcutaneous
injections of morphine (10-40 mg/kg) twice daily for 4 days. The C57B/6J and 129/SVEV
strains exhibited strong analgesia post-injection while the CXBK strain, which has decreased
MOR-1 expression, did not show an analgesic response. Beginning with the third injection day,
the C57B/6J and CXBK strains developed OIH as evident by an increase in pain sensitivity
while the 129/SVEV strain did not develop OIH. An increase in locomotor activity and a
decrease in defecation rates were seen in all three strains of mice. During the time periods in
which the greatest OIH response was observed, spinal cord and brain tissue from multiple
regions was collected and analyzed for MOR-1 and MOR-1K gene expression. The expression
level of MOR-1 was found to be unchanged between the vehicle and morphine-treated mice
while an increase in MOR-1K was observed in the morphine-treated mice only. Upregulation of
the MOR-1K isoform may be causing the switch from the inhibitory effect of morphine to an
excitatory effect at the cellular level leading to the subsequent development of OIH.
Disclosures: M.S. Conrad, None; S. Wentworth, None; D. Prusik, None; J. Gauthier,
None; R. Sukumar, None; W. Maixner, None; L. Diatchenko, None; A. Nackley, None.