The arrival of action potentials in the dorsal horn (DH) of the spinal cord, carrying the sensory information either from nociceptors in inflammation or generated both from nociceptors and intrinsically after nerve damage, produces yet greater complexity in pain and analgesia. Within the CNS, not only are excitatory mechanisms of prime importance but in contrast to much of the peripheral signalling, the role of controlling inhibitory transmitter systems is of paramount importance. Within our spinal cords and brains, not only are the sensory and emotional aspects of pain generated but there are also mechanisms that can make the pain signals stronger (descending facilitation) or weaker (descending inhibition). The main issue here is that the former predominate in most conditions since an absence of pain after trauma is a rare event confined to the short term in situations such as combat or sports events.
A large majority of nocisponsive PAF and many projection neurones contain the major excitatory neurotransmitter glutamate. Glutamate acts at both metabotropic (mGlu) receptors (G-protein coupled) and the ionotropic AMPA, Kainate and NMDA receptors (coupled directly to ion channels). During persistent pain, C-fibers are stimulated repetitively at a high frequency, resulting in wind-up, an amplification and prolongation of the response of spinal DH neurones. In particular, NMDA receptors are thought to play a central role in this sensitization of DH neurones by increasing the synaptic efficacy of nociceptive pathways (long-term potentiation, LTP) and hence underpin hyperalgesia and allodynia .
Spinal LTP therefore presents one likely mechanism by which acute pain becomes chronic .
The development of NMDA receptor antagonists for the treatment of pain has been hampered since the NMDA receptor is essential for normal neuronal function . First-generation NMDA antagonists include ketamine, memantine and dextromethor-phan. This class of low-affinity uncompetitive open channel blockers is thought to inhibit only tonic pathophysiological NMDA receptor activity, leaving phasic physiological activity unaffected [52-55]. Ketamine, originally clinically used as a dissociative anesthetic, can be used at low subanesthetic analgesic doses in a wide range of pain states. When administered at a low dose perioperatively, ketamine spares opioid consumption and reduces opioid-related side effects such as nausea and vomiting , and is also effective as a "rescue analgesic" in acute pain that is poorly responsive to morphine . The use of keta-mine in the treatment of chronic pain, however, is more limited since long-term abuse engenders cognitive impairments of memory, attention and judgment and there is a paucity of data about issues such as tolerance, dependence and withdrawal. However, low-dose intravenous ketamine has proved effective in reducing allodynia associated with post-traumatic pain  and spinal cord injury pain , and patients suffering refractory cancer pain responded wel! to short-term "burst" treatment .
The long-term increase in pain sensitivity frequently seen following injury or peripheral nerve damage is thought to be due to both alterations in transmission within the spinal cord and to changes in descending controls that run back to the spinal cord from the brainstem. Within this circuit, nocic-eptive information is also relayed to higher centers in the brain via projection neurones. The neuroanatomy of these ascending pain pathways is highly complex, and supraspinal contacts include centers involved with the sensory-discriminative aspects of pain such as the intensity, location and duration of the stimulus as well as centers involved in the affective-cognitive aspects including anxiety, emotion and memory . Importantly, these are the same areas of the brain that modulate descending serotonergic and noradren-ergic inputs from the brainstem that regulate nocic-eptive processing at spinal levels. Thus, a network of spinal and brain circuits can change spinal sensitivity to peripheral inputs, and regulation of this by descending pathways from the brain can link the level of cord sensitivity to the behavioral and environmental context. For example, pain can cause anxiety and sleep deficits, and the sensation of pain becomes more intense as a result of this reciprocal regulation. Conversely, "fear conditioning," whereby anticipation in response to re-exposure to a situation previously associated with a noxious stimulus, can activate the endogenous antinociceptive descending pathways and thus provides an important survival response in mammals .
Several classes of antidepressant including serotonin and noradrenaline reuptake inhibitors (SSRIs, SNRIs), and tricyclic antidepressants, in particular amitriptyline, have proved effective in the treatment of certain types of neuropathic pain [63, 64]. The analgesic mechanism of action of antidepressants is not fully understood but it is thought to be independent of their antidepressant effect. Since these agents increase synaptic levels of noradrenaline and 5HT, their central analgesic action is likely to involve either presynaptic mechanisms reducing nociceptive transmission or postsynaptic mechanisms enhancing the endogenous descending inhibitory pathways. Likely targets include the activation of central inhibitory a2-adrenoreceptors and members of the inhibitory 5HT-1 receptor family as well-known analgesics such as the antihypertensive drug clonidine and the triptan family, used in the treatment of migraine, exert their analgesic effects through these receptors respectively [65, 66]. Given that facilitatory 5HT-3 receptors are also present in the dorsal horn , the improved efficacy of SNRIs over SSRIs observed in the treatment of neuropathic pain  may be accredited to this. More recently, a horde of peripheral analgesic targets has also been proposed ; at these sites it is unlikely that the increased availability of 5HT and noradrenaline is accountable since these agents are thought to be pronociceptive at this level.
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