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.