Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Vanilloid (Capsaicin) Receptors and Mechanisms

Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.

A potent and selective endogenous agonist for the mu-opiate receptor.

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Intrathecal morphine in mice: a new technique.

Intrathecal substance P elicits a caudally-directed biting and scratching behavior in mice

Mice were tested for antinociceptive activity after intrathecal injection of opioid or noradrenergic agonists by lumbar puncture. Opioid agonists with mu or delta activity and adrenergic agonists with alpha activity demonstrated dose-related, receptor-mediated analgesia in the tail-flick assay, s.c. hypertonic saline assay and the intrathecal substance P behavioral assay. Inhibition of substance P-induced biting and scratching by intrathecally administered antinociceptive agents is likely mediated by post-synaptic receptors. This action of opioids and norepinephrine was antagonized by their respective pharmacological antagonists. Subanalgesic doses of Leu-enkephalin or norepinephrine potentiated the antinociceptive activity of morphine in the substance P assay. Similarly, opioid agonists potentiated the action of norepinephrine. These results suggest that opioid and alpha adrenergic agonists act on separate receptors to produce a synergistic inhibition of the transmission of nociceptive information at the spinal level.

J. L.K. Hylden

Papers

Intrathecal morphine in mice: a new technique.

Intrathecal substance P elicits a caudally-directed biting and scratching behavior in mice

Pharmacological characterization of substance P-induced nociception in mice: modulation by opioid and noradrenergic agonists at the spinal level.

Intrathecal substance P and somatostatin in rats: behaviors indicative of sensation.

Intrathecal serotonin in mice: analgesia and inhibition of a spinal action of substance P.