Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Abstract

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 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 create 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.

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

“…These constitutively active receptors then mask hyperalgesia that can be revealed with administration of a μ-opioid inverse agonist. 12,45 Collectively, this body of work indicates that neuronal networks mediating acute pain sensitivity directly following injury may not be the same once the organism transitions to a state of pathological pain plasticity. More work is needed to explore this idea more fully; however, it would have important implications for target development and therapeutic discovery.…”

Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice

“…A recent study has shown that μ-opioid receptor agonist-induced antinociceptive effects are not the result of continuous opioid release but rather attributable to the constitutive activity of μ-opioid receptors [28, 29]. These physiological phenomena were also shown in a recent human study [30], and they are known as latent sensitization, which exhibits key features of chronic pain [31]. Latent sensitization may be induced by a wide variety of painful stimuli, including paw incisions [32, 33] and inflammation [28], and these noxious stimuli may lead to a period of hyperalgesia that ranges from several days to months [34].…”

Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons

“…In addition, there has been a broad reliance on observing significant effects with the withdrawal reflex in order for new potential mechanisms to be considered feasible and worthy of more in-depth study. This reliance on the withdrawal reflex remains in spite of its significant limitations and work demonstrating that withdrawal reflex-sensitization can be masked in rodents over the same time course as chronic neuropathic pain would develop (Solway et al, 2011; Taylor and Corder, 2014). The number of animal models in which human-like chronic neuropathic pain is observed is far fewer than the number of conditions known to be associated with chronic pain in humans.…”