The induction of pain: An integrative review

The highly disagreeable sensation of pain results from an extraordinarily c omplex and interactive series of mechanisms integrated at all levels of the nt neuroaxis, From the periphery, via the dorsal horn to higher cerebral s tructures. fain is usually elicited by the activation of specific nocicepto rs ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although ac ute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar infla mmatory mediators, such as prostaglandins and bradykinin, potentially-impor tant, pronociceptive roles have been proposed for a variety of 'exotic' spe cies, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role i n the response to inflammation and injury, and in processes modifying nocic eption. In the dorsal horn of the spinal cord, wherein the primary processi ng of nociceptive information occurs, N-methyl-D-aspartate receptors are ac tivated by glutamate released from nocisponsive afferent fibres. Their acti vation plays a key role in the induction of neuronal sensitization, a proce ss underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exac erbates sensitized states and further enhance laociceptian. As concerns the transfer of nociceptive information to the brain, several pathways other. than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-senso ry' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involve d in the induction of pain, particular attention is focused on cellular asp ects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive inform ation from peripheral nerve terminals to the dorsal horn, and there-from to higher centres, are outlined. This neuronal framework is then exploited fo r a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peri pheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adap tive mechanisms modulating nociception. An improved understanding of the or igins of pain should facilitate the development of novel strategies for its more effective treatment. (C) 1998 Elsevier Science Ltd. All rights reserv ed.