Pain transmits from the periphery to higher brain areas, from which pain messages can be either suppressed (analgesia), relayed unaltered, or amplified (hyperalgesia). Pain modulation occurs in the dorsal horns of the spinal cord, where peripheral nerves relay sensory information to pain transmission neurons (PTNs). It is where the periphery meets the CNS that both analgesia and hyperalgesia are created.4
Neurons are not the only cell type involved in such process. Rather, spinal cord cells called "glia" are also of critical importance. Astrocytes and microglia have not only generally been viewed as cells with the major function of activation in response to centrifugal hyperalgesia circuitry (as below). They are also immunocompetent cells and thus can respond like immune cells within the central nervous system. Microglia express the same surface markers as macrophages/monocytes. Substantial evidence indicates that it can contribute to neuropathic pain after peripheral nerve injury. Indeed, when the glia is activated, a variety of chemical substances are released to amplify pain message, thus causing more painful hurt.58 Microglia are activated by events such as CNS injury, microbial invasion and some pain status, which leads to an increase in the production of various inflammatory cytokines, chemokines and other substances. Many of the substances that can be released from astrocytes and microglia are known to be key mediators of hyperalgesia, including NO, excitatory amino acids (both N-methyl-D-aspartate (NMDA) and non-NMDA agonists), IL-1, IL-6, TNFα, prostaglandins, and NGF.59,60 A relevant study61 showed that intrathecal administrations of CCL2 and IL-1 induce rapid activation and recruitment of macrophages and microglia in the white matter of the spinal cord that is undergoing Wallerian degeneration, which might, in turn, affect pain processing.
Spinal cord astrocytes and microglia are key mediators of pathogen-induced hyperalgesia. They express specific receptors for some infectious agents like various bacteria and viruses. For example, glial activation will be induced by neurotropic virus (that is, a virus that can "home" to the brain and spinal cord) such as HIV-1 that are known to invade the central nervous system.62 HIV-1 invades the brain and spinal cord early in, and continuing throughout, disease progression,63 and this invasion leads to the activation of astrocytes and microglia.64 Tsuda et al65 showed that the activation of microglia in neuropathy requires P2X4 receptors, which are upregulated and specifically expressed by microglia in neuropathic pain models. P2X7 receptors' activation can lead to the production and release of inflammatory cytokines. However, the mice without this receptor show an impaired ability to develop neuropathic pain.66 A recent study67 suggested that TLR4 might contribute to painful neuropathy. This receptor is activated by several exogenous and endogenous ligands such as LPS, heat-shock proteins, the extradomain A of fibronectin and amyloid. Compared with wild-type mice, TLR4-knockout and point-mutant mice did not develop thermal and mechanical allodynia after peripheral nerve injury, together with reduced microglial and astrocyte activation, remarkbly decreased expression of interferon (IFN), IL-1,and TNF.
Peripheral infection/inflammation leads to activation of a brain-to-spinal cord pathway, culminating in the creation of hyperalgesia. This spinal circuitry also critically depends on the activation of spinal cord astrocytes and microglia. Anatomically, astrocytes and microglia are clearly activated by peripheral infection/inflammation, as evidenced immunohis- tochemically by increased expression of glia-specific activation markers.32 The released cytokines (TNF and IL-6) might be involved in microglial activation. IL-1 could activate microglia, which could, in turn, release pronociceptive compounds and/or directly influence pain pathways. The recruitment of microglia is commonly associated with the activation (phosphorylation) of p38 MAP kinase.68 Phosphorylation of p38 is probably a key intracellular signal in microglia, which regulates pain-related actions. Hyperalgesia can be blocked by spinal administration of drugs that disrupt glial function.32,69 Peripheral cytokines lead to the production of central cytokines, which will participate in the mediation of central components of sickness.
Several studies have shown that specific microglia and astrocyte inhibitors and/or modulators can block and/or reverse neuropathic status. The most commonly used compounds are fluorocitrate and minocycline. Previous studies have shown that pre-emptive and curative fluorocitrate treatment (selectively blocks astrocyte and microglia metabolism) inhibits neuropathic pain,70 whereas minocycline (a specific microglial inhibitor) blocks the development of neuropathic pain but does not reduce pain that is already established.71 Watkins et al69,72 reported that intrathecal minocycline was much more effective in delaying the induction of allodynia than in reversing it in models of sciatic inflammatory neuropathy and acute spinal immune activation with intrathecal HIV-1 gp120. Moreover, the spinal implantation of microglia that had been activated in vitro simulated signs of neuropathic pain (mechanical allodynia).65 These studies indicate that microglia might be more important in the initial phases of neuropathic pain. Microgial activation might be the first step in a cascade of immune responses in the CNS. It might be responsible for the initiation of neuropathic pain status, and astrocyte may be involved in their maintenance.
The glia may be activated by neurotransmitters released by spinal projections of the nucleus raphe magnus. Candidate neurotransmitters to serve this role are substance P and glutamate.62 Once activated, astrocytes and microglia form a positive feedback circuit whereby substances released from microglia activate astrocytes to release substances that further stimulate microglia, and so forth.