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 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.

Figures

Figure 1. Opioidergic signaling

Opioid agonists bind to the extracellular binding pocket of opioid receptors to activate intracellular inhibitory G-proteins (Gαi/o—βγ). Dissociated G-proteins can reduce neuronal excitation and/or neurotransmitter release via inhibition of adenylyl cyclases (AC), voltage-gated calcium channels (VGCC), and activation of inward-rectifying potassium channels (GIRK). Red blunted lines indicate inhibition and blue arrows indicate activation.

Figure 2. Minipump infusion of NTX increases the duration of mechanical hyperalgesia, indicating that endogenous opioid receptor activity hastens the resolution of inflammatory pain

Changes in mechanical pain resolution after continual minipump infusion of saline or NTX (10 mg / kg /d) for 14d in Sham and CFA mice (n = 4 - 7 per group). * P Adapted from Corder et al, 2013.

Figure 3. NTX reinstates inflammatory pain even when administered 6 months after induction of inflammation

After baseline (BL) measurement of von Frey threshold, mechanical hypersensitivity was allowed to recover (red circles). Effect of repeated subcutaneous saline (open circles) or NTX (3 mg /kg, blue circles) injections on mechanical thresholds at 21, 49, 77, and 105d after CFA (n = 5 – 7). Adapted from Corder et al, 2013.

Figure 4. Constitutive activity and inverse agonism

(a) The Extended Ternary Complex model of GPCR signaling which predicts that modulating the allosteric constant (red arrows) produces a spontaneously active receptor (Ra). Ra can then bind to G-proteins (G) independent of agonist (A) facilitation (pink arrows). (b) Effect of various ligands on GPCR activity.

Figure 5. Spinal μ-opioid receptors acquire constitutive activity (MORCA) after injury

(A) Dose-response effects of β-FNA intrathecal β-funaltrexamine (β-FNA) on basal GTPγS35 binding in lumbar dorsal horns of Sham or CFA-21d mice; inset: group binding Emax (n = 7 - 9). (B) Effects of intrathecal administration of NTX (1 ug), 6β-naltrexol (10 ug), or co-administration of 6β-naltrexol+NTX in sham and post-hyperalgesia mice on mechanical hyperalgesia. * P<0.05. Adapted from Corder et al, 2013.

Figure 6. NMDAR are required for NTX-induced pain reinstatement and are sensitized during the remission phase of latent pain sensitization

(A). Effect of intrathecal administration of the NMDAR antagonist, MK-801 (1 ug) on NTX-precipitated mechanical hyperalgesia (n=5-10). (B) Effect of NMDA (i.t.; 3 pmol) on spontaneous nocifensive behaviors (left) and paw flinches (right) over 15 min in Sham (n=5) and CFA (n=5) mice. *p<0.05. Adapted from Corder et al, 2013.

Figure 7. Endogenous opioid withdrawal initiates NMDAR-dependent AC superactivation

(A) Effect of intrathecal administration of NMDA (i.t.; 3 pmol) on cAMP levels in Sham (n=5) and CFA (n=5) mice, indicating a latent up-regulation of an NMDAR-AC pathway during the remission phase of LS. (B) Effect of intrathecal administration of MK-801 (3 pmol) pretreatment on NTX-induced cAMP overshoot, indicating that NMDAR signaling contributes to AC superactivation during NTX-precipitated endogenous opioid withdrawal (n=5 per group). *p<0.05. Adapted from Corder et al, 2013.

Figure 8. Superactivation of spinal AC1 faciltates pain reinstatement and cellular opioid withdrawal

Effect of intrathecal administration of the AC1 antagonist, NB001 (1.5 ug), on NTX-precipitated mechanical hyperalgesia (A) and spinal cAMP content (D). Effect of the AC activator, forskolin (intrathecal, 1.5 ug( on spontaneous nocifensive behaviors (B) and paw flinches (C) over 15 min in sham and CFA mice, indicating AC1 superactivation during the remission phase of LS. n=6-9. *p<0.05. Adapted from Corder et al, 2013.

Figure 9. Cellular signaling pathways underlying opioid receptor-masked latent sensitization

Spinal cord MOR signaling, through inhibitory Gai/o proteins, tonically represses AC1 production of cAMP, thereby reducing nociceptive signal transduction. Blockade of MOR results in the disinhibition of AC1, allowing for NMDAR-derived, Ca2+-mediated activation and downstream increases in signal transduction, neuron excitability, and ultimately, pain. Adapted from Corder et al, 2013.

Figure 10. Schematic summarizing the sequence of events that occur after injury, leading to a dynamic relationship between the systems that regulate analgesia and pain

Under naïve conditions nociceptive and opioidergic systems have little to no activity, resting at a basal set point (homeostasis). Several changes occur following injury or strong nociceptive input. First, Severe tissue injury triggers the development of an opioid receptor-masked LS that is driven by NMDA NR2 subunit and AC1/Epac1-mediated signaling (Green line). Second, a compensatory, counter-adaptation -- constitutively active μ-opioid receptor analgesia (Blue line, MORCA) -- enables the resolution of pain (red line) and thus maintains LS in a state of remission. The intensity and degree of sensory information transmitted through the nociceptive system returns to pre-injury levels while the opponent processes are potentiated but functionally cancel out one another. Third, if this balance is perturbed, e.g. upon inverse agonism of MORCA (dotted line), then blockade of tonic MOR signaling produces a superactivation of the NMDAR—AC1 pathways and LS can be visualized as pain reinstatement. Thus, pain is only detectable when endogenous analgesia is removed, leaving LS unchecked. Fourth, the body gradually becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Pain begets MORCA begets pain in a vicious cycle. As a result, the nociceptive system becomes dependent on the counterbalancing signaling of tonic MOR. A recurring failure of MORCA (ie during stress) may reflect the transition from acute pain to a chronic state of pain vulnerability.