Chifuyu Takeshige

Cutaneous hyperalgesia induced by peripheral injection of interleukin-1β in the rat

The contribution of the activity of afferent fiber filaments to pain and hyperalgesia after administration of a plantar injection of interleukin-1 beta (IL-1 beta) to the hind-paw skin was investigated by recording action potentials of the rat dorsal root in response to mechanical and thermal stimuli. Touch stimuli were delivered by stroking with a cotton-tipped applicator and thermal stimulation was applied by cooling or heating of the skin. After the administration of IL-1 beta (100 pg-1 microgram), responses to touch, cold, and heat stimulation increased to 143%, 200%, and 392%, respectively, of control values on average. IL-1 beta induced transient spontaneous discharge in 50% of experiments. The effects of IL-1 beta were apparent within 1 min. To examine responses to pressure stimulation, an area of 1 mm2 of the hind-paw skin was pressed by a mechanical stimulator. IL-1 beta (0.1 pg-200 ng) decreased the threshold value to 58% of the control pressure required for firing. IL-1 beta also increased responses to various levels of pressure (range: 1-20 g/mm2). These data suggest that IL-1 beta may play an important role in cutaneous hyperalgesia by activating polymodal receptors to mechanical and thermal stimulation.

Descending pain inhibitory system involved in acupuncture analgesia

The descending pain inhibitory system (DPIS) associated with acupuncture analgesia (AA), caused by low frequency stimulation of an acupuncture point, was identified by the results of lesion and stimulation procedures previously determined to differentiate the afferent and efferent paths in rats. The DPIS starts in the posterior arcuate nucleus and descends to the hypothalamic ventromedian nucleus (HVM) from whence it divides into two pathways: one path, the serotonin mediated path, descends through the ventral periaqueductal central gray (V-PAG) and then to the raphe magnus (RM). The other, the noradrenaline mediated path, descends through the reticuloparagigantocellular nucleus (NRPG) and part of the reticulogigantocellular nucleus (NRGC). The afferent and efferent paths are both present in the RM and NRGC, and were separately identified by means of the analgesia (SPA) produced by stimulation of the separate regions in AA responders and nonresponders, because SPA of these regions in nonresponders produced only efferent pathway mediated analgesia.

The acupuncture point and its connecting central pathway for producing acupuncture analgesia

Characteristics of the acupuncture point in producing acupuncture analgesia (AA) were examined by the inhibition of noxious responses in the brain stem reticular formation, potentials, and neuronal activity in the dorsal periaqueductal central gray (D-PAG), and analgesia caused by low frequency stimulation of the acupuncture point. As a result, stimulation of the muscle beneath the acupuncture point was found to be effective in producing AA. AA measured by tail flick, vocalization, and writhing tests was abolished by hypophysectomy, and by antiserum of beta-endorphin administered into the 3rd ventricle. The pathway from the D-PAG to the anterior hypothalamus (AA-AH) in the AA afferent pathway from the acupuncture point to the pituitary gland was determined. The lateral hypothalamus, lateral septum, cingulate bundle, dorsal-hippocampus, and habenulo-interpeduncular tract were found, in addition to regions previously found, to belong to the AA afferent pathway. A network of divergence and convergence in their rostral and caudal relations was observed. The AA afferent pathway diverges from the D-PAG, converges to the HP, and then projects to the AA-AH.

Diode laser irradiation selectively diminishes slow component of axonal volleys to dorsal roots from the saphenous nerve in the rat

Ga-Al-As laser irradiation (830 nm wavelength) inhibits the action potentials in the dorsal roots elicited from the saphenous nerve of the rat. Following laser irradiation to the saphenous nerve, the amplitude of slower conduction parts of action potentials (conduction velocity < 12 m/s) were suppressed. This suppression was irradiation time dependent. After 3 min irradiation, slowest conduction velocity group (< 1.3 m/s) were totally diminished and 1.3-12 m/s group were reduced to 12-67%. In contrast, faster component (> 12 m/s) was unaffected by laser irradiation. These findings suggest that laser irradiation may selectively target fibers conducting at slow velocities which include afferent axons from nociceptors.

Laser irradiation abates neuronal responses to nociceptive stimulation of rat-paw skin

The effects of diode laser irradiation on peripheral nerves was examined by monitoring neuronal discharges elicited by application of various stimuli to the hind-paw skin of rats. Neuronal discharges elicited by brush, pinch, cold, and/or heat stimulation, as well as chemical stimulation by injection of turpentine (0.1 ml, SC) were recorded from L5 dorsal roots in urethane-anesthetized rats. Diode laser irradiation (830 nm, 40 mW, 3 min, continuous wave) of the saphenous nerve exposed from the muscle of the lower leg significantly inhibited neuronal discharges elicited by pinch (68.4 +/- 6.5%), cold (45.4 +/- 9.2%), and heat stimulation (49.2 +/- 11.3%). Neuronal discharges induced by brush stimulation (104.3 +/- 4.7%) were not affected by laser irradiation. Injection of turpentine, a chemical irritant, into the hind-paw skin (0.1 ml, SC) elicited neuronal discharges in the ipsilateral dorsal root, and these discharges were significantly inhibited or abolished by laser irradiation. In 6- to 7-week-old rats treated neonatally with capsaicin (10 mg/kg, SC), injection of turpentine into the hind-paw skin did not elicit neuronal discharges and laser irradiation did not affect the background discharges. These data suggest that laser irradiation may selectively inhibit nociceptive neuronal activities.

Activation of the satiety center by auricular acupuncture point stimulation

Stimulation of the rat inner auricular regions that correspond to the human pylorus, lung, trachea, stomach, esophagus, endocrine, and heart acupuncture points evoked potentials in the hypothalamic ventromedial nucleus (HVM), the satiety center. Needle implantation into any of these points reduced the body weight to its initial 290 g after the rat had gained about 410 g in 20 days, and significantly reduced initial 450-g body weights (p less than 0.01, Students t test) in 14 days. Stimulation of other acupuncture points did not evoke HVM potentials and did not reduce body weight. After the HVM was lesioned, body weight increased and acupuncture point needling had no effect on body weight. Needling of the auricular acupuncture points evoked no potentials in the lateral hypothalamus (LHA), the feeding center, and had almost no influence on weight reduction induced by LHA lesion.

Analgesia inhibitory system involvement in nonacupuncture point-stimulationproduced analgesia

Acupuncture analgesia (AA), caused by low-frequency stimulation of an acupuncture point (AP)--in this case the tibial muscle--was augmented. Nonacupuncture analgesia (NAA), caused under certain circumstances by stimulation of a nonacupuncture point (NAP)--in this case the abdominal muscle--was unmasked by lesion in the lateral centromedian nucleus of the thalamus (L-CM) or part of the posterior hypothalamus (I-PH). Stimulation in these regions suppressed the augmented part of the AA and blocked the NAA. These regions were, collectively, given the name analgesia inhibitory system. NAA was abolished, the same as AA, by hypophysectomy. The pathways from the AP and NAP to the pituitary gland were different. AA was naloxone reversible, and NAA was dexamethasone reversible. The analgesia inhibitory system is activated nonspecifically by stimulation of either an AP or NAP. It ascends to the I-PH, thence to the L-CM, and ultimately inhibits the pathway nonspecifically connected to the NAP and AP in the lateral part of the periaqueductal central gray (PAG), without affecting the pathway specifically connected to the AP. Thus, only stimulation of an AP will produce analgesia, whereas stimulation of an NAP will not normally produce analgesia. Stress-induced analgesia (SIA) is produced in a different way than AA or NAA.

Positive feedback action of pituitary β-Endorphin on acupuncture analgesia afferent pathway

Potentials in the final sector of the afferent pathway from the acupuncture point (AP) were enhanced by intraperitoneal 0.5 mg/kg morphine without changing the threshold of AP stimulation and greatly decreased by hypophysectomy. The decreased potentials were restored to the control level by morphine (0.5 mg/kg, IP). Potentials evoked in the final sector of the afferent pathway from the nonacupuncture point (NAP) by NAP stimulation after lesion of the analgesia inhibitory system were greatly enhanced by corticotropin (ACTH) (0.25 mg/kg, IP) and greatly decreased by hypophysectomy. Diminished potentials were restored to the control level by ACTH (0.25 mg/kg, IP). Both morphine (0.5 mg/kg, IP) and ACTH (0.25 mg/kg, IP) produced analgesia, but morphine did not affect acupuncture analgesia (AA) and ACTH did not affect nonacupuncture point stimulation-produced analgesia (NAA). All analgesia, that due to 0.5 mg/kg morphine or 0.25 mg/kg ACTH, AA, and NAA were abolished by hypophysectomy. The abolished AA and NAA were restored by 0.5 mg/kg morphine and 0.25 mg/kg ACTH, respectively. Hence, beta-E and ACTH liberated from the pituitary gland by stimulation of an AP and NAP may act as positive feedback on the AA and NAA afferent pathways, respectively.

PARALLEL INDIVIDUAL VARIATIONS IN EFFECTIVENESS OF ACUPUNCTURE, MORPHINE ANALGESIA AND DORSAL PAG-SPA AND THEIR ABOLITION BY D-PHENYLALANINE

Individual variations in effectiveness of acupuncture analgesia(AA), morphine analgesia(MA) and dorsal periaqueduct central gray stimulation-produced analgesia(d-PAG-SPA) were parallel. Close correlation was also observed between the individual variations of AA effectiveness and morphine-like-factors(MLF) in the brain. Individual variations in effectiveness of these analgesia were diminished by D-phenylalanine (D-phe).

Dopaminergic transmission in the hypothalamic arcuate nucleus to produce acupuncture analgesia in correlation with the pituitary gland

Acupuncture analgesia (AA) caused by low frequency stimulation of the acupuncture point (AP) was abolished by hypophysectomy and adrenalectomy. Termination of the AA producing pathway from the AP to the pituitary gland was in the medial hypothalamic arcuate nucleus (M-HARN). The origin of the descending pain inhibitory system associated with AA was in the posterior HARN (P-HARN). AA in the hypophysectomized rats, and enhanced neuronal activity in the P-HARN that were abolished during acupuncture stimulation, were both restored by intraperitoneal microinjection of 0.5 mg/kg morphine or 0.1 micrograms beta-endorphin into the P-HARN during acupuncture stimulation. Of the analgesia produced by dopamine or beta-endorphin injected into the P-HARN, that caused by beta-endorphin disappeared after denervation of the M-HARN. The P-HARN neurons that responded to acupuncture stimulation also responded to iontophoretic dopamine, but not to iontophoretic morphine nor ultramicroinjected beta-endorphin. The transmission between the M-HARN and P-HARN may be dopaminergic, and beta-endorphin might presynaptically modulate this transmission. Reduction of sodium ions may have been the reason for abolition of AA after adrenalectomy.