We currently have several projects ongoing in the lab related to pain and addiction. Two of these are highlighted below.
Cognitive disruption resulting from acute and chronic pain.
We are interested in understanding the effects of pain on outcomes that go beyond simple reflexive withdrawal behaviors which primarily rely on local spinal circuitry. We are particularly interested in behaviors mediated by the frontal cortex, such as attention, impulse control, and executive function. For these studies we utilize a variant of the classical 5 choice serial reaction time task that automatically adjusts task difficulty to match performance capabilities of the subject in real time.1 We have demonstrated that the dorsomedial prefrontal cortex is active during performance of this task, and that either increased basal activation by audiovisual distraction or inhibition of activation by acute incisional pain disrupt performance in this task, which requires sustained visual attention.2,3 Disruption by either acute abdominal inflammatory pain or incisional pain is reversed by morphine, confirming the role of pain per se in disruption of attention in this task.3,4 Moving forward, we are examining the effects of chronic neuropathic pain and the role of noradrenergic input to the medial prefrontal cortex using these behavioral measures of sustained attention. We hope to elucidate circuitry influenced by chronic pain and the role of incoming nociceptive signals on supraspinal circuits in nonreflexive behavioral measures that limit the ability of animals to perform routine tasks. To this end we have developed and characterized novel surfaces that stimulate high threshold mechanoreceptors selectively in injured afferents, which can be utilized in conjunction with operant assays to ask such questions.5 These studies are supported by P01-GM113852 from NIGMS/NIH (Eisenach).
- Martin TJ, Grigg A, Kim SA, Ririe DG, Eisenach JC: Assessment of attention threshold in rats by titration of visual cue duration during the five choice serial reaction time task. J Neurosci Methods 2014; 241C: 37-43
- Ririe DG, Boada MD, Schmidt BS, Martin SJ, Kim SA, Martin TJ: Audiovisual Distraction Increases Prefrontal Cortical Neuronal Activity and Impairs Attentional Performance in the Rat. J Exp Neurosci 2017; 11: 1179069517703080
- Ririe DG, Boada MD, MacGregor MK, Martin SJ, Strassburg TJ, Kim SA, Eisenach JC, Martin TJ: Incisional Nociceptive Input Impairs Attention-related Behavior and Is Associated with Reduced Neuronal Activity in the Prefrontal Cortex in Rats. Anesthesiology 2018
- Martin TJ, Strassburg TJ, Grigg AL, Kim SA, Ririe DG, Eisenach JC: Assessment of Behavioral Disruption in Rats with Abdominal Inflammation Using Visual Cue Titration and the Five-choice Serial-reaction Time Task. Anesthesiology 2017; 127: 372-381
- Boada MD, Martin TJ, Ririe DG: Nerve injury induced activation of fast-conducting high threshold mechanoreceptors predicts non-reflexive pain related behavior. Neurosci Lett 2016; 632: 44-49
Cognitive disruption in animals relapsing to cocaine self-administration.
Using methods similar to those cited above, we are interested in understanding how relapse to cocaine self-administration following periods of abstinence induces cognitive disruption in attention, impulse control, and executive function. Using the same visual attention task, we have found that relapse to intermittent cocaine self-administration following periods of abstinence induces two behavioral phenotypes, one vulnerable to deficits in sustained visual attention and another that is resilient. These phenotypes emerge despite no differences in overall cocaine intake through self-administration. We are currently exploring different drug classes that might serve as appropriate pharmacological remediation strategies, as well as basic mechanisms in the medial prefrontal cortex responsible for these two distinct phenotypes. Basic mechanisms being explored relate to mTORC1 signaling and associated synaptic remodeling in the medial prefrontal cortex, which appears to be correlated with behavioral phenotype in this visual attention task. These latter studies are being explored in conjunction with Dr. Kimberly Raab-Graham in the Department of Physiology and Pharmacology at Wake Forest School of Medicine, and are supported by P50-DA-006634 (Nader).
John WS, Martin TJ, Nader MA. Behavioral Determinants of Cannabinoid Self-Administration in Old World Monkeys. Neuropsychopharmacology. 2017 Feb 01. PMID: 28059083.
Brust TF, Morgenweck J, Kim SA, Rose JH, Locke JL, Schmid CL, Zhou L, Stahl EL, Cameron MD, Scarry SM, Aubé J, Jones SR, Martin TJ, Bohn LM. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal. 2016 Nov 29; 9(456):ra117. PMID: 27899527.
Boada MD, Martin TJ, Ririe DG. Nerve injury induced activation of fast-conducting high threshold mechanoreceptors predicts non-reflexive pain related behavior. Neurosci Lett. 2016 Oct 06; 632:44-9. PMID: 27544012.