Endogenous Analgesia, Dependence, and Latent Pain Sensitization

  • Bradley K. Taylor
  • Gregory Corder
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 20)


Endogenous activation of µ-opioid receptors (MORs) provides relief from acute pain. Recent studies have established that tissue inflammation produces latent pain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic, and aversive signs of physical withdrawal; this phenomenon requires N-methyl-d-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury. First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains the accelerator) and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization creates a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic pain by either (a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission, or (b) extinguishing LS altogether.


Pain Adenylyl cyclase NMDA receptor Latent sensitization Opioid Analgesia Constitutive activity Dependence Addiction Post-operative pain Central sensitization Stress 



The authors thank Charles Anderson for construction of Fig. 10 in Illustrator and Howard Fields and Tony Yaksh for helpful discussions. This work was supported by NIH grants F31DA032496 (G.C.), K02DA19656 (B.K.T.), and R21DA38248 (B.K.T.)


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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Physiology, School of MedicineUniversity of Kentucky Medical CenterLexingtonUSA
  2. 2.Department of Anesthesiology, Perioperative and Pain MedicineStanford UniversityStanfordUSA
  3. 3.Department Molecular and Cellular PhysiologyStanford UniversityStanfordUSA

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