Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies

Abstract

Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long-term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids' lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non-opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.

Keywords: analgesia; opioid receptors; opioid tolerance; opioid-induced hypersensitivity; opioids; pain.

FIGURE 1

Anatomy of the pain processing pathway (From Cellular and Molecular Mechanisms of Pain, Basbaum et al., Cell, 2009, 139:267–284. With permission from Elsevier). ¹⁷ Primary afferent nociceptors convey noxious information to projecting neurons in the dorsal horn (DH) of the spinal cord. A subset of these projecting neurons transmits information to the somatosensory cortex via the thalamus providing physical information about the painful stimulus (the primary ascending pathway, in green). Other projection neurons (in blue) relay via brainstem structures to engage the insular and cingulate cortex, contributing to the affective and cognitive components of pain. The ascending information is also able to interact with several other brain/brainstem areas, such as the rostral ventral medulla (RVM) and midbrain periaqueductal gray (PAG) to engage descending feedback systems that regulate the output of projecting neurons in the DH (in orange)

FIGURE 2

The PAG‐RVM descending system under normal conditions. In the naïve state, GABAergic interneurons are tonically active, thus both PAG output neurons and OFF‐cells have low spontaneous firing rates. Activity in OFF‐cells causes antinociception, and activity in ON‐cells represents descending facilitation of pain. The normal activity of ON‐cells is also low, such that the overall balance between ON‐cell and OFF‐cell output to the dorsal horn (DH) is equal and there is no net hypersensitive or antinociceptive state in the individual

FIGURE 3

Intracellular signaling in naïve PAG GABAergic interneurons, and following acute morphine administration (reproduced with permission from Lueptow et al. 2018 ³⁹ ). In the naïve state. GABAergic interneurons are tonically active and release the inhibitory neurotransmitter GABA. GABA acts through GABA_A receptors on PAG output neurons. GABA_A receptors are inhibitory by causing an influx of chloride ions which hyperpolarizes and therefore inhibits the PAG output neurons. Following acute morphine administration. MORs initiate a variety of downstream signaling cascades in the interneurons. Postsynaptically, MORs activate G‐protein‐coupled inwardly rectifying potassium ion channels (GIRKs), hyperpolarizing the neuron. Both Gα_i and Gβγ are important in regulating the activity of GIRK. Gα_i directly binds to the GIRK channel, stabilizing it and priming it for Gβγ activation. ⁴⁰ Presynaptically, MORs inhibit voltage‐gated calcium channels (VGCCs) via the Gβγ subunit. Inhibition by Gβγ is voltage‐dependent and large or repeated depolarizations of the presynaptic terminal could overcome the inhibition. ⁴¹ Gβγ also activates voltage‐gated potassium channels (Kv's) via a mechanism involving phospholipase A (PLA). The overall effect of decrease calcium ion influx and increased potassium ion efflux is hyperpolarization and inhibition of neurotransmitter release, therefore decreasing GABA‐mediated inhibition of output neurons

FIGURE 4

Intracellular adaptations produced by chronic morphine use in GABAergic interneuron in the PAG (reproduced with permission from Lueptow et al. ³⁹ ). Postsynaptically, there may be some uncoupling between the G proteins and MORs, a process distinct from acute homologous desensitization (Melief et al. ⁴⁹ ; Bruchas et al. ⁵⁰ ), therefore decreased activation of GIRKs. Presynaptically, superactivation of AC results in PKA‐mediated phosphorylation of VGCCs, and therefore increased calcium conductance. The overall effect is increased GABA release and therefore stronger inhibition of PAG output neurons

FIGURE 5

Calcium conductance through VGCCs in naïve, acute, and chronic morphine/withdrawal GABAergic interneurons in the PAG. The average resting membrane potential in PAG interneurons is −60 mV. ⁵¹ A, the naïve neuron in blue . a modest level of calcium conductance (arbitrary units, AU) is present. The calcium influx triggers calcium‐dependent exocytosis and neurotransmitter release. Hence naïve PAG interneurons tonically release GABA. B, acute morphine in red . following acute activation of MOR, inhibition of AC‐cAMP‐PKA signaling results in dephosphorylation of VGCCs and direct binding of Gβγ causes a right‐ward shift in the activation of VGCCs. Furthermore, the opening of potassium channels by morphine hyperpolarizes the interneurons (approximately −70 mV). The combination of these two factors results in very low conductance through the VGCCs and inhibition of GABA release. C, chronic morphine in green . superactivation of AC causes overactivation of PKA that can phosphorylate VGCCs. Phosphorylation by PKA increases the probability of channel opening, allowing for calcium influx even in hyperpolarized neurons ⁵²

FIGURE 6

Linear circuit involved in the development of neuropathic pain (as described by Huang et al. ⁶⁵ ). Peripheral nerve injury augments basolateral amygdala (BLA) inputs onto GABAergic interneurons located in the medial prefrontal cortex (mPFC). This augmentation is the result of weakened endocannabinoid signaling. Decreased CB₁ receptor density was observed in BLA‐originating presynaptic terminals. Increased activity in mPFC inhibitory interneurons leads to an overall inhibition of excitatory pyramidal cell output toward vlPAG output neurons. The net effect is decreased descending inhibition via the RVM to the spinal cord

FIGURE 7

The P2X4‐BDNF‐KCC2 pathway involved in OIH (reproduced with permission from Trang et al. 2015). The binding of morphine (or other MOR agonists) to MORs on spinal microglia activates pro‐inflammatory cascades in the microglia. Microglia activation induces P2X4 receptor upregulation, and morphine causes the release of BDNF through ATP‐mediated stimulation of P2X4 receptors. BDNF acts through TrkB on dorsal horn lamina I neurons to downregulate the expression of KCC2. This disrupts chloride homeostasis in the DH by preventing chloride efflux via KCC2. The increased intracellular chloride concentration in lamina I neurons shifts GABA receptor activation from inhibitory to excitatory ⁹⁰

FIGURE 8

The various signaling outcomes following MOR activation. G‐protein‐dependent signaling following MOR activation involves the G‐protein subunits pre‐bound to the receptor, in the case of MOR, this is usually the Gα_i and Gβγ subunits. Acutely, MOR activation inhibits adenylyl cyclase (AC) through Gα_i, but chronic MOR activation appears to over‐activate AC. Desensitization, internalization, recycling, and downregulation involve agonist‐induced receptor phosphorylation, for example, through GRK. β‐arrestin is recruited by phosphorylated residues of MOR. β‐arrestin binding can trigger clathrin‐mediated internalization of the receptor. MORs in endosomes can either be recycled to the plasma membrane or broken down (downregulation). β‐arrestin can act as a scaffold to activate G‐protein‐independent signaling cascades (in red), for example, extracellular signal‐regulated kinases (ERKs), c‐Jun N‐terminal kinases (JNKs), Src, and PKC ¹⁰⁶