Negative feedback is an important mechanism whereby the organism maintains its balance in a complicated system. It may be regarded as a modern version of the ancient Eastern wisdom of Yin and Yang balance. Control of pain and analgesia, is no exception: CCK seems to serve as a built-in mechanism for the modulation of opioid analgesia system [dickenson].

The authors presume that activity in the dorsal horn or nociceptors is well correlated with pain sensations and behavior. This overlooks the myriad of interactions between cortex and our spinothalamic tract. It is better to think of our nociceptors, the dorsal horn, and the pain centers in our brain as all components in one larger and complex pain sensory system. [berkley; blumberg et al.; coderre & katz; dickenson; mcmahon; wiesenfeld-hallin et al.]

Plastic changes in spinal cord function like neuronal wind-up and increased receptive field are too short-lived to explain chronic pain without structural changes. It is possible that learning could be a mechanism for longlasting changes in nociceptive regulation. A learning process localized to the spinal cord has been shown to be important for the development of tolerance to the analgetic effect of ethanol, suggesting that nociceptive control systems may be changed by learning. Long term potentiation (LTP) is regarded as a useful model of learning and memory. LTP-like changes have been observed in in vitro preparations from the spinal cord and in spinal cord field potentials. Recently a long term increase in spinal A-β and C-fibre evoked responses after painful stimulation has been observed. [coderre & katz, dickenson, wiesenfeld-hallin et al.]

Central sensitization and related neurochemical mechanisms are also induced in V nociceptive pathways after craniofacial injury or inflammation. Their characteristics raise additional possibilities that may explain some of the phenomena outlined by coderre & katz, dickenson, and wiesenfeld-hallin et al. They also underscore the need for therapeutic approaches to reduce nociceptive inputs to the CNS or their neuroplastic effects which can potentially enhance post-traumatic pain.

This commentary provides experimental data in support of the critical role of capsaicin-sensitive primary afferent fibers in the initiation and maintenance of pathological pain. The demonstration of capsaicin-induced, centrally-evoked cutaneous hyperalgesia, and of neuroplastic changes elicited by the degeneration of C-fiber primary afferent terminals following peripheral nerve damage, indicates a significant contribution of capsaicin-sensitive sensory ganglion neurons in the development of pathological pain conditions. [coderre & katz]

The belief that women report more somatic complaints than men is not new. Many centuries b.c., the Egyptians and the Greeks already made an association between female pains and hysteria, which is Greek for “wandering womb.” Despite the commonly held belief that women are more sensitive to pain than men, the issue of sex differences in pain has received little attention from the scientific community in general. It is the merit of berkley to draw our attention to this large gap in our scientific knowledge.

According to berkley's review, women have a higher risk of suffering from pain than men. If this is true, there should be more frequent and more intense activity both in the pain excitatory system and in the pain inhibitory system of women than of men. Consequently, it remains unclear whether the overall effect at the end is more pain or less pain in women. This conclusion fits the weak sex differences observed for experimental and clinical pain as shown by berkley's review of the literature.

Abundant pathophysiological and clinical evidence suggests that the algogenic code responsible for cardiac pain is not based on “specific” mechanisms (mcmahon). Recent evidence, however, has led various authors to postulate that some degree of specificity might be involved in visceral pain arising from other sources, but a “spatio-temporal” intensity pattern is still the most plausible hypothesis for the genesis of visceral pain.

My commentary on mcmahon addresses the fact that only peripheral data have been considered for explaining differential sensibility in somato- and viscerosensory systems. This fails to take it into account that central processing for visceral and somatic inputs is now known to depend on different functional pathways. My commentary on berkley points out that the hypothalamus-pituitary axis is more responsive to stress in females than in males.

The central hyperexcitability observed in animal models supports a pathophysiological explanation for chronic human pain. Novel information on cholecystokinin (CCK) upregulation offers a rationale for reduced opioid response in neuropathic pain. However, the basic information provided by scientists should not lead clinicians to equate experimental models to chronic human conditions. Clinicians should provide careful reports and attempt to classify pathophysiologically clinical conditions that have so far been grouped generically. [blumberg et al.; coderre & katz; dickenson; wiesenfeld-hallin et al.]

It is argued by berkley that there are theoretical reasons why sex differences in pain may result from specific learning processes. I argue that Berkley has not gone far enough in pursuing this suggestion, and that the evidence that learning is a major determinant of pain behaviour is substantial. Moreover, sex differences in pain may represent only a special case of individual differences in pain resulting from learning processes.

Numerous mediators are involved in both the control and the transmission of nociceptive messages, and several lines of research have been developed in the management of pain. Complete enkephalin- degrading enzyme inhibitors, which produce naloxone-reversible analgesia in all tests where morphine has been found to be active, remains the most promising way. CCK compounds, especially the CCKB antagonists also may be interesting drugs. Indeed, they are able to strongly potentiate the antinociceptive effects of the opioids. [dickenson, wiesenfeld-hallin et al.]

Neuroplastic changes in the inhibitory systems contribute to pathological pains such as hyperalgesia. Activation or inhibition of the intrinsic inhibitory systems may depend on the pathophysiology which induces a sustained pain state. The mechanisms of hyperalgesia, opioid insensitivity following nerve injury, and opioid tolerance may be related to common neuroplastic changes. [wiesenfeld-hallin et al.]

Recent studies indicate a role of the sympathetic nervous system in acute and chronic pain. However, the terminology of the clinical sympathetically maintained pain (SMP) syndromes continues to be confusing and the criteria for diagnosis of SMP are being refined. (blumberg et al.) Despite significant progress in recent years, the mechanisms of the interaction between the sympathetic and sensory systems in SMP remain puzzling.

This commentary on blumberg et al. addresses complications associated with diagnostic testing for sympathetic dependence of pain that can lead to inappropriate positive and negative conclusions. In addition, it is suggested that their “ischemic” test be conceived as a test of the effect of local vascular pressure and that the two types of sensory disorders presented may differ primarily in the degree of sensitization of central pain pathways. Detailed reports with functionally-oriented testing like that done by blumberg are essential for an understanding the pathophysiological mechanisms.

The evidence favoring sex differences in pain seems compelling (berkley). This commentary considers the role of such factors as anxiety, somatosensory amplification, and coping style in accounting for the differential response to pain in the laboratory and clinic, and emphasizes the need to base evaluation and treatment upon individual reports rather than gender-based stereotypes.

The possible dysfunction of γ aminobutyric acid (GABA) and opioid inhibitory mechanisms following central and peripheral nervous system injury is an important and potentially useful finding. However, effective clinical application must take into account the specific characteristics of the models used in the studies and the relationship of these models to specific clinical conditions. [dickenson; wiesenfeld-hallin et al.]

dickenson briefly mentions that peripheral opioid receptors somehow become active following inflammation and that the appearance of endogenous opioid peptides at the injury site may be related to immune cell proliferation. Recent findings elucidate the underlying mechanisms in more detail and provide an incentive for the development of a novel generation of analgesics devoid of typical central opioid side effects.

This commentary addresses the strength of the comparative approach to the study of sex differences in pain. Animal studies can focus our attention on mechanisms of sex differences in these clinical sex differences. Important sex differences are seen in descending pain modulation, thereby providing an explanation for the observation of sex differences in pain perception. [berkley]

berkley's line of reasoning about sex and pain experience suggests a completely different perspective on sex differences in human experimental, clinical, and epidemiological pain research. Although physiological mechanisms may place women at greater risk for pain, women may have found ways to dampen the effect of these mechanisms. Nevertheless, it is a challenge to extrapolate physiological mechanisms in human phenomena from outcomes observed in animal models.