Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

This paper reviews architectonic subdivisions and connections of the orbital and medial prefrontal cortex (OMPFC) in rats, monkeys and humans. Cortico-cortical connections provide the basis for recognition of 'medial' and 'orbital' networks within the OMPFC. These networks also have distinct connections with structures in other parts of the brain. The orbital network receives sensory inputs from several modalities, including olfaction, taste, visceral afferents, somatic sensation and vision, which appear to be especially related to food or eating. In contrast, the medial network provides the major cortical output to visceromotor structures in the hypothalamus and brainstem. The two networks have distinct connections with areas of the striatum and mediodorsal thalamus. In particular, projections to the nucleus accumbens and the adjacent ventromedial caudate and putamen arise predominantly from the medial network. Both networks also have extensive connections with limbic structures. Based on these and other observations, the OMPFC appears to function as a sensory-visceromotor link, especially for eating. This linkage appears to be critical for the guidance of reward-related behavior and for setting of mood. Imaging and histological observations on human brains indicate that clinical depressive disorders are associated with specific functional and cellular changes in the OMPFC, including activity and volume changes, and specific changes in the number of glial cells.

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The Organization of Networks within the Orbital and Medial Prefrontal Cortex of Rats, Monkeys and Humans

Converging evidence now indicates that the amygdala plays a crucial role in the development and expression of conditioned fear. Conditioned fear is a hypothetical construct used to explain the cluster of behavioral effects produced when an initially neutral stimulus is consistently paired with an aversive stimulus. For example, when a light, which initially has no behavioral effect, is paired with an aversive stimulus such as a footshock, the light alone can elicit a constellation of behaviors that are typically used to define a state of fear in animals. To explain these findings, it is generally assumed (cf. McAllister & McAllister 1971 ) that during light-shock pair­ ings (training session ), the shock elicits a variety of behaviors that can be used to infer a central state of fear (unconditioned responses-Figure 1 ). After pairing , the light can produce the same central fear state and thus the same set of bchaviors formerly produced by thc shock. Moreover, the behavioral effects that are produced in animals by this formerly neutral stimulus (now called a conditioned stimulus-CS ) are similar in many respects to the constellation of behaviors that are used to diagnose gener­ alized anxiety in humans (Table 1 ). This chapter summarizes data sup­ porting the idea that the amygdala, and its many efferent projections, may represent a central fear system involved in both the expression and acquisition of conditioned fear.

The role of the amygdala in fear and anxiety

The formalin test: an evaluation of the method.

The organization of afferent projections to the midbrain periaqueductal gray of the rat

In vivo microdialysis was used to sample extracellular concentrations of amino acids in the dorsal lumbar spinal cord of freely moving rats. Changes in the extracellular concentrations of amino acids were measured in response to infusion of veratridine (180 μM), a sodium channel activator, as well as during acute noxious stimulation by an injection of 5% formalin into the metatarsal region of the hindleg. Veratridine produced a tetrodotoxin (TTX)-sensitive increase in the extracellular concentration of Glu. Concentrations of Asp, taurine, Ala, Asn, and Gly were not significantly elevated following veratridine stimulation. In-tradermal injection of formalin produced a TTX-sensitive increase in Asp concentration and a non-TTX-sensitive increase in Glu concentration. These data support the hypothesis that Glu and Asp are dorsal horn neurotransmitters involved in nociception.

Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation

Bee venom (BV) has traditionally been used in Oriental medicine to relieve pain and to treat inflammatory diseases such as rheumatoid arthritis (RA). While several investigators have evaluated the anti-inflammatory effect of BV treatment, the anti-nociceptive effect of BV treatment on inflammatory pain has not been examined. Previous studies in experimental animals suggest that the therapeutic effect of BV on arthritis is dependent on the site of administration. Because of this potential site specificity, the present study was designed to evaluate the anti-nociceptive effect of BV injections into a specific acupoint (Zusanli) compared to a non-acupoint in an animal model of chronic arthritis. Subcutaneous BV treatment (1 mg/kg per day) was found to dramatically inhibit paw edema caused by Freund's adjuvant injection. Furthermore, BV therapy significantly reduced arthritis-induced nociceptive behaviors (i.e. the nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia). These anti-nociceptive/anti-inflammatory effects of BV were observed from 12 days through 21 days post-BV treatment. In addition, BV treatment significantly suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3 weeks post-adjuvant injection. Finally, injection of BV into the Zusanli acupoint resulted in a significantly greater analgesic effect on arthritic pain as compared to BV injection in to a more distant non-acupoint. The present study demonstrates that BV injection into the Zusanli acupoint has both anti-inflammatory and anti-nociceptive effects on Freund's adjuvant-induced arthritis in rats. These findings raise the possibility that BV acupuncture may be a promising alternative medicine therapy for the long-term treatment of rheumatoid arthritis.

Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses.

This paper describes a model of tumor-induced bone destruction and hyperalgesia produced by implantation of fibrosarcoma cells into the mouse calcaneus bone Histological examination indicates that tumor cells adhere to the bone edge as early as post-implantation day (PID) 3, but osteolysis does not begin until PID 6, correlating with the development of hyperalgesia C3H/He mice exhibit a reproducible hyperalgesia to mechanical and cold stimuli between PID 6 and 16 These behaviors are present but significantly reduced with subcutaneous implantation that does not involve bone Systemic administration of morphine (ED(50) 90 mg/kg) dose-dependently attenuated the mechanical hyperalgesia In contrast, bone destruction and hypersensitivity were not evident in mice implanted with melanoma tumors or a paraffin mass of similar size A novel microperfusion technique was used to identify elevated levels of the putative algogen endothelin (ET) in perfusates collected from the tumor sites of hyperalgesic mice between PID 7 and 12 Increased ET was evident in microperfusates from fibrosarcoma tumor-implanted mice but not from melanoma tumor-implanted mice, which are not hyperalgesic Intraplantar injection of ET-1 in naive and, to a greater extent, fibrosarcoma tumor-bearing mice produced spontaneous pain behaviors, suggesting that ET-1 activates primary afferent fibers Intraplantar but not systemic injection of the ET-A receptor antagonist BQ-123 partially blocked tumor-associated mechanical hyperalgesia, indicating that ET-1 contributes to tumor-induced nociception This model provides a unique approach for quantifying the behavioral, biochemical, and electrophysiological consequences of tumor-nerve interactions

https://www.jneurosci.org/content/jneuro/21/23/9355.full.pdf

Functional Interactions between Tumor and Peripheral Nerve: Morphology, Algogen Identification, and Behavioral Characterization of a New Murine Model of Cancer Pain

Alvin J. Beitz

Papers

The organization of afferent projections to the midbrain periaqueductal gray of the rat

Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation

Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses.

Functional Interactions between Tumor and Peripheral Nerve: Morphology, Algogen Identification, and Behavioral Characterization of a New Murine Model of Cancer Pain

Nitric oxide synthase-containing neural processes on large cerebral arteries and cerebral microvessels.