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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    828—Pain Models: Pharmacology II

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    828.23: Pain relief increases dopamine efflux in the nucleus accumbens

    Location: Halls B-H

    ">*J. Y. XIE1, D. LU2, C. QU2, D. J. WASIAK2, B. S. SILVER2, J. OYARZO2, N. GOSHIMA2, P. HERNANDEZ2, F. PORRECA2, E. NAVRATILOVA2, M. H. OSSIPOV2, F. PORRECA2;
    1Dept. of Pharmacol., Univ. of Arizona, TUCSON, AZ; 2Pharmacol., Univ. of Arizona, Tucson, AZ

    Abstract Body: We have previously used conditioned place preference (CPP) to unmask ongoing (i.e., “spontaneous”) pain that may be present in injured rats. In humans, relief of pain is rewarding. Consistent with this, we showed that pain relief following peripheral nerve block (PNB) in rats with incisional injury produced CPP and activated the mesolimbic dopaminergic reward pathway. PNB produced CPP and increased dopamine (DA) efflux in the nucleus accumbens (NAc) shell only in injured rats. Here, we have explored whether other treatments that produce pain relief also produce increases in DA efflux in the NAc in animals with experimental neuropathic pain induced by tight ligation of the L5/L6 spinal nerves (SNL injury). While both spinal clonidine and adenosine reversed tactile hypersensitivity in nerve-injured rats, only clonidine induced CPP. We used the same treatments in animals with SNL injury to determine if NAc DA was altered by these treatments. Adult male Sprague-Dawley rats received SNL as well as implantation of intrathecal catheters and a guide cannula directed at the NAc. After 7 days, in vivo microdialysis was performed in awake, freely moving rats by infusing artificial cerebrospinal fluid through a microdialysis probe placed into the left NAc shell. Dialysate was collected continuously in 30 min fractions and analyzed with HPLC. Basal DA levels in NAc microdialysate from SNL and sham-operated rats were 0.17 ± 0.01 and 0.18 ± 0.02 pg/µl respectively (p>0.05). Spinal clonidine (3, 6 and 10 µg) dose-dependently increased NAc DA level in SNL, but not sham-operated rats with a maximal increase of approximately 61% at the 30-60 min fraction. In contrast, spinal adenosine did not alter NAc DA levels in either sham or SNL treatment groups. In order to confirm that effective pain relieving treatments would be reflected by enhanced NAc DA efflux, we evaluated gabapentin (GBP, 300 mg/kg, p.o.) in sham and SNL rats. This dose of GBP reversed the tactile hypersensitivity in SNL rats and prevented the CPP elicited by spinal clonidine, suggesting effective relief of ongoing pain. Correspondingly, the NAc DA level was elevated by systemic GBP in SNL, but not sham-operated rats. The peak change from baseline was approximately 45% at the 150-180 min fractions and the AUC value was 4241 ± 1214 (p<0.05 vs. sham-operated or SNL vehicle groups). The data suggest that treatments that produce apparent relief of ongoing pain increase DA efflux in the NAc shell reflecting likely activation of the reward circuitry (i.e., relief of pain is rewarding). Thus, NAc DA efflux might represent a neurochemical assay that could be predictive of relief of ongoing pain.

    Lay Language Summary: A potential biomarker of pain relief -increased dopamine release from the reward circuits
    We have discovered that the increase of dopamine (DA) release from the brain reward pathway by non-abused drugs might be used as an objective, quantifiable output measure (i.e. biomarker) for the relief of ongoing pain. A biomarker of “pain relief” would provide an entirely new way to evaluate novel mechanisms for treatment of pain and may increase bench-to-bedside translation.
    While neuroscientists have learned a lot about pain, this has not led to the discovery of many new medications to help the millions of people whose lives are affected by chronic pain.
    In an effort to find better therapeutic reagents, we have been exploring new preclinical measures that may better reflect features of the human experience including, especially, the unpleasantness of pain. As a part of this effort, we searched for a “biomarker” that signals the relief of ongoing pain. Such a biomarker could be used to identify, filter and increase confidence in mechanisms that may translate across species and that can serve as the basis for development of new therapies.
    Relief of pain is a reward in humans and in animals. We have studied pain and reward circuits in rats and demonstrated that clinically validated pain relieving treatments can selectively activate reward circuits only in the presence of pain. When paired with a context, pain-relieving treatments reinforce behavior (Navratilova et al., PNAS, 2012). The current study further extends this concept by demonstrating that increase of DA levels in the nucleus accumbens (NAc) shell, a key output structure of the reward pathway, may be used as a surrogate marker indicative of relief of ongoing pain selectively in injured rats.
    We used a “reverse translation” strategy to test drugs that have been demonstrated clinically to be effective or ineffective in post-surgical or neuropathic pain. These pain states were modeled in rats with hindpaw incision (post-surgical pain) or experimental nerve injury (neuropathic pain). Extracellular DA levels in the NAc shell were captured by in vivo microdialysis in awake, freely moving rats and quantified by HPLC.
    We found that in rats with experimental neuropathic pain, clinically effective treatments such as intrathecal clonidine or systemic gabapentin dose-dependently increased NAc DA levels while ineffective treatments including intrathecal adenosine or systemic naproxen (a non-steroidal anti-inflammatory drug, NSAID) did not. Also consistent with clinical use, in rats with post-surgical pain, naproxen and other NSAIDs produced long-lasting increase of the DA levels in NAc, but gabapentin failed to do so.
    Importantly, these drugs activated the reward pathway only in the presence of pain. No increases in NAc DA were detected in sham-operated rats. This observation is consistent with the concept that relief of pain is a reward. The drugs producing this effect are not associated with addiction in humans or in animals.
    Our studies suggest that relief of pain aversiveness produces negative reinforcement of behavior along with engagement of reward pathways. Evaluation of these circuits by putative pain relieving mechanisms provides an entirely new pathway for discovery of pain therapies with high translational relevance.