“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

Abstract

It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons.

Induction of Thermal Hyperalgesia and Synaptic Long-Term Potentiation in the Spinal Cord Lamina I by TNF-α and IL-1β is Mediated by Glial Cells

“…We found that both cytokines enhanced synaptic AMPAR-and/or NMDAR-mediated currents in lamina I neurons and induced LTP in a significant proportion of neurons. Amplification of synaptic strength between C-fibers and lamina I (present study) and lamina II neurons (Kawasaki et al, 2008;Park et al, 2011;Zhang et al, 2011) by IL-1␤ and/or TNF-␣ are potential mechanisms underlying the hyperalgesia that can be evoked by either of these cytokines (Watkins et al, 1994;Sung et al, 2004;Kawasaki et al, 2008).…”

“…Cytokine receptors may be expressed on neurons and/or glial cells (Li et al, 2005;Xu et al, 2006;Guo et al, 2007;Wei et al, 2008;. Therefore, cytokines do not necessarily modify synaptic strength directly by binding to presynaptic and/or postsynaptic receptors.…”

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

“…After a stimulus has resolved, experimental evidence suggests microglia remain "primed", entering a sensitised state in which they do not actively produce pro-inflammatory substances, yet they over-respond to subsequent stimuli, increasing pro-inflammatory cytokine release and exaggerating pain. [94][95][96] Activation of spinal microglia and astrocytes has been demonstrated in virtually every clinically relevant animal model of an enhanced pain state 88 with similar results reported for trigeminal pain models. 97 Moreover, glial-attenuating pharmacological interventions are able to block the phenotypic transformation of glial cells into the activated state and prevent both allodynia and hyperalgesia across a diverse range of pre-clinical pathological pain models.…”

“…[85][86][87] It is likely that other glial cell types are also involved in pain facilitation, however research to date has focused upon astrocytes and microglia, as they are the most amenable to study. 88,89 An incontrovertible wealth of pre-clinical data show when exposed to stimuli, such as central nervous system (CNS) trauma, ischaemia, neurodegeneration or the immunological components of pathogens, microglial cells rapidly become 'activated', i.e. they develop an ability to perform a function beyond that which they are able to perform in the baseline state.…”

The role of glial cells in influencing neurite extension by dorsal root ganglion cells

“…Current studies provide evidence of bidirectional influence between neurons and these glial cells (Fields and Stevens-Graham, 2002;Nave and Trapp, 2008). Indeed, glial cells of the central nervous system are now viewed as a crucial third element of the synapse, and may be similarly important in the peripheral nervous system (Vesce et al, 2001;Watkins et al, 2007;Filippo et al, 2008). Given the heterogeneous nature of a typical preparation of DRG cells, this study aimed to identify whether the PTX-dependent neurite retraction response was specific to any one of the three subpopulations of neurons and to determine whether the non-neuronal cells were involved in regulating this response.…”