Pain is not a single entity but is instead a collection of sensory experiences commonly associated with tissue damage. There is growing recognition that not all pains are equivalent, that pains and pathologies are not related in a simple manner, and that acute pains differ in many respects from persistent pains. Great strides have been made in improving our understanding of the neuronal mechanisms responsible for acute pain, but the studies leading to these advances have also led to the realization that a bewildering array of processes are interposed between tissue damage and sensations of pain, especially in persistent pains. Persistent pains often seem unrelated or disproportionate to identifiable pathology, and they are modulated by a multitude of factors. This complexity in such a vital function serves as a challenge both to scientists seeking fundamental understanding and to clinicians faced with the immediate need to treat patients with painful disorders.

Are there sex differences in pain? For experimentally delivered somatic stimuli, females have lower thresholds, greater ability to discriminate, higher pain ratings, and less tolerance of noxious stimuli than males. These differences, however, are small, exist only for certain forms of stimulation and are affected by many situational variables such as presence of disease, experimental setting, and even nutritive status. For endogenous pains, women report more multiple pains in more body regions than men. With no obvious underlying rationale, some painful diseases are more prevalent among females, others among males and, for many diseases, symptoms differ between females and males. Sex differences in attitudes exist that affect not only reporting, coping, and responses to treatment, but also measurement and treatment. So many variables are operative, however, that the most striking feature of sex differences in reported pain experience is the apparent overall lack of them. On the other hand, deduction from known biological sex differences suggests that these are powerful sex differences in the operation of pain mechanisms. First, the vaginal canal provides an additional route in women for internal trauma and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, sex differences in temporal patterns are likely to give rise to sex differences in how pain is “learned” and stimuli are interpreted, a situation that could lead to a greater variability and wider range of pains without obvious peripheral pathology among females. Third, sex differences in the actions of sex hormones suggest pain-relevant differences in the operation of many neuroactive agents, opiate and nonopiate systems, nerve growth factor, and the sympathetic system. Thus, while inductive analysis of existing data demonstrate more similarities than differences in pain experience between females and males, deductive analysis suggests important operational sex differences in its production.

There are some conspicuous differences between the sensibilities of cutaneous and visceral tissues: (1) Direct trauma, which readily produces pain when applied to the skin, is mostly without effect in healthy visceral tissue. (2) Pain that arises from visceral tissues is initially often poorly localised and diffuse. (3) With time, visceral pains are often referred to more superficial structures. (4) The site of referred pain may also show hyperalgesia. (5) In disease states, the afflicted viscera may also become hyperalgesic. In this target article, I consider to what extent differences in the physiology, anatomy, and chemistry of peripheral processing systems explain these different sensibilities. In almost every aspect, there are subtle differences in the properties of the processing mechanisms for cutaneous and visceral information. These may arise because of distinct developmental cues operating in the two domains. Many of the differences between visceral and cutaneous afferents are quantitative rather than qualitative. The quantitative differences, for example in the density of afferent innervation, can be large. The quantitative differences in the numbers of afferents alone may be a sufficient explanation for some aspects of the differential sensibility, for example, the poor localisation of sensation and the apparent insensitivity to focal yet tissue- damaging stimuli. In addition, the few clear qualitative differences apparent in the innervations of the two tissue types may be of special importance. That the encoding of visceral nociceptive events may occur by an intensity mechanism rather than a specificity mechanism could be the key difference in viscerosensory and somatosensory processing.

The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors – therefore opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature.

This target article examines the clinical and experimental evidence for a role of peripheral and central hyperexcitability in persistent pain in four key areas: cutaneous hyperalgesia, referred pain, neuropathic pain, and postoperative pain. Each suggests that persistent pain depends not only on central sensitization, but also on inputs from damaged peripheral tissue. It is instructive to think of central sensitization as comprised of both an initial central sensitization and an ongoing central sensitization driven by inputs from peripheral sources. Each of these factors, initial sensitization, ongoing central sensitization, and inputs from peripheral sources, contributes to the net activity in dorsal horn neurons and thus influences the expression of persistent pain or hyperalgesia. Since each factor, peripheral inputs and central sensitization (initial or ongoing), can contribute to both the initiation and maintenance of persistent pain, therapies should target both peripheral and central sources of pathology.

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the γ-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called “reflex sympathetic dystrophy” (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called “sympathetically maintained pain” (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic–sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied.

Dysfunction or injury of pain-transmitting primary afferents' central pathways can result in pain. The organism as a whole responds to such injury and consequently many symptoms of neuropathic pain develop. The nervous system responds to painful events and injury with neuroplasticity. Both peripheral sensitization and central sensitization take place and are mediated by a number of biochemical factors, including genes and receptors. Correction of altered receptors activity is the logical way to intervene therapeutically. [berkley; blumberg et al.; coderre & katz; dickenson; mcmahon; wiesenfeld-hallinet al.]

Complex regional pain syndromes (reflex sympathetic dystrophy, causalgia) are often characterized by pain and autonomic and motor abnormalities. Pathophysiological mechanisms are in the central and peripheral nervous system. Differences in skin temperature and “the ischemia test” may be used as diagnostic criteria. Sympathetic blocks relieve pain and other symptoms in a subgroup of patients (sympathetically maintained pain, SMP). [blumberg et al.]

Both the sensory and the motivational-affective component of pain must be taken into account in studies on sex differences as well as on neuropathic, postoperative, sympathetic, and visceral pain. In all these cases, therapeutic strategies should be aimed at controlling the peripheral, central, and psychological mechanisms underlying the global pain experience. Similarly, it should be recalled that some neuropeptides act on both sensory and affective pain mechanisms. [berkley; mcmahon; dickenson; coderre & katz; wiesenfeld-hallin et al.; blumberg et al.]

The target articles by blumberg et al. and berkley reflect some of the recent major theoretical and clinical advances in two areas of pain research. These two articles also represent two very different approaches to which type of variables are considered relevant to the study of pain. These different approaches are contrasted in the context of the different emphases in pain and pleasure research.

The persistence of both inflammatory and neuropathic pain can only be explained when learning processes are taken into account in addition to sensitizing mechanisms. Learning processes such as classical and operant conditioning create memories for pain that are based on altered synaptic connections in supraspinal structures and persist without peripheral input. [coderre & katz; dickenson; wiesenfeld-hallin et al.]

berkley's pathogen model of sex differences in pain is inconsistent with women outliving men by several years. The vagina is far more resistant to pathogens than is the rectum. Vaginal stimulation produces intense analgesia in rats and humans. Possible evolutionary and cardiovascular factors are also noted.

Recent pain research has concentrated heavily on excitatory processes. However, noxious stimuli activate excitatory and inhibitory systems. As failure of inhibition could underlie some forms of pathological pain, it may be argued that a full understanding of the mechanisms underlying the development of pain states can only come from a consideration of all the central sequelae of injurious stimuli. [berkley; blumberg et al.; coderre & katz; dickenson; mcmahon; weisenfeld-hallin et al.]

Hyperalgesia can arise from peripheral sensitization, on-going peripheral activation, and central plasticity. In the target article, coderre & katz argue that all three mechanisms contribute to hyperalgesia. In contrast, we believe that existing experimental evidence suggests that central plasticity plays only an insignificant role in most experimental models and clinical presentations of hyperalgesia induced by tissue injury or chemical activation of sensory receptors.

Evidence that central sensitization needs to be maintained in an ongoing manner by nociceptive input from the periphery makes the peripheral drive, rather than the central amplification process, the highest priority target for understanding and control. To stop the peripheral drives to kill two birds with one stone. Moreover, the amplification that central sensitization does provide is selective and not necessarily striking in intensity. A “magic bullet” that neutralized central sensitization would probably be less effective in controlling persistent pain than many investigators would like to believe. [berkley; blumberg et al.; coderre & katz; dickenson; mcmahon; weisenfeld-hallin et al.]

Patients with reflex sympathetic dystrophy (RSD) affecting one limb show similar sympathetic traffic in nerves supplying the affected and unaffected limb, despite unilateral autonomic effector dysfunction. This argues against the notion that RSD is mediated by a reflex change in the pattern of sympathetic discharge and underlines the fact that autonomic effector disturbances give little information about underlying nerve traffic. [blumberg et al.]

Signal-detection methodology may be used to disentangle sensory from judgmental effects when analyzing sex differences in pain. An illustrative example is given by reanalyzing a published category-scaling experiment in terms of detection-theory indices. As a result, the apparent sex difference is recast in terms of a judgmental bias. [berkley]

The argument of berkley for the existence sex differences in pain is based on biological factors. We suggest that the psychological evidence for such differences is more substantial.

In patients with pain characterized by a painful focus and allodynia, the painful symptoms arise from altered central processing that is initiated and subsequently maintained by persistent input from nociceptive afferents. Treatments directed at this normal consequence of persistent input are inherently limited. The most efficacious treatments will target the pathology, the various sources of ongoing nociceptor input. [blumberg et al.; coderre & katz; dickenson]