Long-Chuan Yu

Repeated massage-like stimulation induces long-term effects on nociception: contribution of oxytocinergic mechanisms.

Massage‐like stroking induces acute antinociceptive effects that can be reversed by an oxytocin antagonist, indicating activation of oxytocin on endogenous pain controlling systems. We now demonstrate an increase in hindpaw withdrawal latencies (HWLs), in response to thermal and mechanical stimuli, which was present after six treatments of massage‐like stroking every other day and which continued to increase through the remaining seven treatments. Repeated massage‐like stroking also resulted in increased oxytocin‐like immunoreactivity (oxytocin‐LI) levels in plasma and periaquaductal grey matter (PAG). Furthermore, increases in HWLs were also present after injections of oxytocin into the PAG (0.1, 0.5 and 1.0 nmol). Intra‐PAG oxytocin injection of 1 nmol followed by 1 or 20 nmol of naloxone attenuated the increments in HWL. Also, there was a dose‐dependent attenuation of the oxytocin‐induced antinociceptive effects following intra‐PAG injection of the µ‐opioid antagonist β‐funaltrexamine (β‐FNA) and the κ‐opioid antagonist nor‐binaltorphimine (nor‐BNI) but not the δ‐antagonist naltrindole. The long‐term antinociceptive effects of massage‐like stroking may be attributed, at least partly, to the oxytocinergic system and its interaction with the opioid system, especially the µ‐ and the κ‐receptors in the PAG.

Intrathecal CGRP8–37‐induced bilateral increase in hindpaw withdrawal latency in rats with unilateral inflammation

1 Recent work in our laboratory has demonstrated that intrathecal administration of a selective antagonist of calcitonin gene‐related peptide (CGRP), CGRP8–37, increased the hindpaw withdrawal latency (HWL) to thermal stimulation and hindpaw withdrawal threshold (HWT) to pressure in normal rats, and that these effects were more pronounced than in rats with mononeuropathy. 2 The present study was performed to investigate the effects of intrathecal administration of CGRP8–37 on the HWL and HWT in rats with unilateral hindpaw inflammation induced by subcutaneous injection of carrageenin. The effect of naloxone was also studied. 3 Subcutaneous injection of 0.1 ml of carrageenin into the plantar region of the left hindpaw induced a significant increase in the volume of the ipsilateral hindpaw (P < 0.001), and significant bilateral decreases of the HWL to thermal stimulation (ipsilateral: P<0.001; contralateral: P<0.01) and HWT to pressure (ipsilateral: P<0.001; contralateral: P<0.01). 4 Intrathecal administration of 10 nmol of CGRP8–37, but not of 1 or 5 nmol, induced a significant bilateral increase in the HWL and HWT in rats with experimentally induced inflammation (thermal test: P<0.001; mechanical test: P<0.001). 5 The effect of intrathecal administration of 10 nmol CGRP8–37 on HWL and HWT was significantly more pronounced in intact rats than in rats with experimentally induced inflammation (ipsilateral: P<0.001; contralateral: P<0.001). 6 The effect of CGRP8–37 on withdrawal responses in the inflamed paw was partly reversed by intrathecal injection of naloxone at a dose of 88 nmol in the thermal (ipsilateral: P<0.01; contralateral: P = 0.14) and mechanical tests (ipsilateral: P<0.05; contralateral: P = 0.60). 7 A significant bilateral increase in the concentration of CGRP‐like immunoreactivity in the perfusate of both hindpaws was demonstrated 24 h after unilateral injection of carrageenin (ipsilateral: P<0.001; contralateral: P<0.05). There was also an increase in the amount of CGRP‐like immunoreactivity in the cerebrospinal fluid (P<0.001), but not in plasma (P=0.75). 8 The present study demonstrates that acute experimentally‐induced unilateral hindpaw inflammation, induces bilateral increases in the amount of CGRP‐like immunoreactivity in hindpaw perfusates. Intrathecal administration of CGRP8–37 increased the HWL to thermal stimulation and HWT to pressure bilaterally. 9 The results indicate that CGRP plays a role in the transmission of presumed nociceptive information in the spinal cord of rats with experimentally induced inflammation. Furthermore, our findings suggest that opioids can modulate CGRP‐related effects in the spinal cord.

Blockade effect of mu and kappa opioid antagonists on the anti-nociception induced by intra-periaqueductal grey injection of oxytocin in rats.

Intra-periaqueductal grey (PAG) injection of 1 nmol of oxytocin induced significant increases in hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats. The anti-nociceptive effect of oxytocin was attenuated significantly by subsequent intra-PAG injection of the mu opioid antagonist beta-funaltrexamine (beta-FNA) and the kappa opioid antagonist nor-binaltorphimine (nor-BNI), but not by the delta antagonist naltrindole. The results demonstrated that mu and kappa opioid receptors, not delta receptors, were involved in the oxytocin-induced anti-nociception in PAG of rats.

The calcitonin gene-related peptide antagonist CGRP8–37 increases the latency to withdrawal responses bilaterally in rats with unilateral experimental mononeuropathy, an effect reversed by naloxone

The present study was performed in rats with experimental mononeuropathy after left common sciatic nerve constriction. A bilateral decrease in hindpaw withdrawal latency to thermal and mechanical stimulation was observed after unilateral ligation of the left common sciatic nerve; however, it was more pronounced on the lesioned side. Compared with sham-operated rats, the content of calcitonin gene-related peptide-like immunoreactivity was significantly decreased in the left dorsal horn of the spinal cord and left dorsal root ganglia in rats with mononeuropathy. Blocking the receptor of calcitonin gene-related peptide, by intrathecal injection of 5 or 10 nmol of calcitonin gene-related peptide (8-37), induced a significant bilateral increase in hindpaw withdrawal latency to both thermal and mechanical stimulation which, however, was significantly less pronounced in mononeuropathic rats than in intact rats. The effect of calcitonin gene-related peptide (8-37) was reversed by intrathecal administration of the opioid antagonist naloxone. The contribution of calcitonin gene-related peptide and its receptors to transmission of presumed nociceptive information appears to be reduced in the sciatic nerve constriction model. The decrease in reflex responsiveness induced by calcitonin gene-related peptide (8-37) was counteracted by naloxone, indicating that opioids control the net effect of excitation in the spinal cord circuitry induced by calcitonin gene-related peptide and possibly other co-released neurotransmitters.

Involvement of oxytocin in spinal antinociception in rats with inflammation

The present study was conducted on rats with inflammation induced by subcutaneous injection of carrageenan into the left hindpaw. Intrathecal administration of oxytocin produced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats with inflammation. The antinociceptive effect of oxytocin was blocked by intrathecal administration of atosiban, a selective oxytocin antagonist, indicating that oxytocin receptor mediates oxytocin-induced antinociception in the spinal cord. The oxytocin-induced antinociceptive effect was attenuated by intrathecal administration of the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Furthermore, the antinociceptive effect of oxytocin was attenuated by intrathecal injections of the mu-receptor antagonist beta-funaltrexamine and the kappa-receptor antagonist nor-binaltorphimine, but not by the delta-receptor antagonist naltrindole, illustrating that mu- and kappa-receptors, but not delta-receptor, are involved in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Moreover, intrathecal administration of atosiban alone induced a hyperalgesia in rats with inflammation, indicating that endogenous oxytocin is involved in the transmission and regulation of nociceptive information in the spinal cord of rats with inflammation. The present study showed that both exogenous and endogenous oxytocin displayed antinociception in the spinal cord in rats with inflammation, and mu- and kappa-receptors were involved in oxytocin-induced antinociception.

The calcitonin gene-related peptide antagonist CGRP8–37 increases the latency to withdrawal responses in rats

The present study explored the effects of calcitonin gene-related peptide (CGRP) and its antagonist CGRP8-37 on the latency to hindpaw withdrawal responses induced by both thermal and mechanical stimulation in rats. (1) Intrathecal injection of 10 nmol of CGRP had no effects on the latency to hindpaw withdrawal; intrathecal injection of 5 nmol of substance P (SP) decreased the latency to both withdrawal responses. (2) Intrathecal administration of 5 nmol or 10 nmol of CGRP8-37, but not 1 nmol, induced a significant increase in hindpaw withdrawal latency. (3) Intrathecal administration of CGRP8-37 not only reversed the SP-induced decrease in latency to both withdrawal responses but also mediated a significant increase in response latency compared to basal levels. The demonstrated results suggest that intrathecal administration of CGRP8-37 has a possible antinociceptive effect, and CGRP receptors in the spinal cord may be involved.

Substance P microinjected into the periaqueductal gray matter induces antinociception and is released following morphine administration

The aims of the present study were to investigate, in rats, the behavioral effects of substance P (SP) microinjected into the ventrolateral periaqueductal gray (PAG) and the effects of the neurokinin 1 (NK-1) receptor antagonist [d-Arg1, d-Trp7, 9, Leu11]-substance P (Spantide). The effect of morphine administration on the release of SP in the ventrolateral PAG was also investigated using microdialysis in awake rats. SP microinjected into the ventrolateral part of the PAG induced significant increases in the hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulation as an antinociceptive response. The NK-1 receptor antagonist blocked these effects but exhibited no antinociceptive effect alone. Subcutaneous administration of morphine increased basal SP-like immunoreactivity (SP-LI) release in the microdialysate obtained from the ventrolateral PAG of freely moving rats. Our results demonstrate that SP injected into the ventrolateral PAG induces an antinociceptive effect via activation of NK-1 receptors. Morphine administered systemically induces the release of SP in the ventrolateral PAG. We suggest that an increased release of SP in the PAG may contribute to opioid antinociception.

Involvement of opioid receptors in the oxytocin-induced antinociception in the central nervous system of rats.

Recent studies showed that oxytocin and opioid peptides play important roles in pain modulation at different levels in the central nervous system. The present study was performed to explore whether opioid system is involved in the oxytocin-induced antinociception in the brain of rats. The results showed that: (1) intracerebroventricular injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWL) to noxious thermal and mechanical stimulation in rats. (2) The antinociceptive effect of oxytocin was attenuated dose-dependently by intracerebroventricular injection of naloxone, indicating an involvement of opioid system in the oxytocin-induced antinociception. (3) It is interesting that the antinociceptive effect of oxytocin was attenuated by subsequent intracerebroventricular injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA) and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI), but not the delta-opioid antagonist naltrindole. The results indicate that oxytocin plays an antinociceptive role in the brain of rats; mu- and kappa-opioid receptors, not delta-receptors, are involved in the oxytocin-induced antinociception in the central nervous system of rats.

Antinociceptive role of galanin in periaqueductal grey of rats with experimentally induced mononeuropathy.

The present study was performed in rats with experimentally induced mononeuropathy after left common sciatic nerve ligation. The hindpaw withdrawal latencies to thermal and mechanical stimulation increased significantly after intra-periaqueductal grey injection of 2 or 3nmol, but not 1nmol of galanin in rats with mononeuropathy. Intraperitoneal administration of 4.5mg/kg morphine induced significant increases in hindpaw withdrawal latencies to both noxious stimulation, which were attenuated by following intra-periaqueductal grey injection of 2nmol of the galanin antagonist galantide. Furthermore, the antinociceptive effect induced by intra-periaqueductal grey injection of 26.6nmol of morphine was attenuated significantly by following intra-periaqueductal gray administration of 2nmol of galantide. The results demonstrated that in periaqueductal grey galanin plays an antinociceptive role in rats with mononeuropathy and galanin is involved in the mechanisms of opioid-induced antinociception.

EFFECTS OF INTRATHECAL GALANIN ON NOCICEPTIVE RESPONSES IN RATS WITH MONONEUROPATHY

The present study was performed on rats with experimental mononeuropathy induced by left common sciatic nerve loose ligation. Unilateral sciatic nerve loose ligation induced decreases of the hindpaw withdrawal latency to the hot-plate test, cold-plate test and the Randall Selitto test. Sciatic nerve loose ligation induced hyperesponsiveness to touch at room temperature also. Intrathecal administration of either 3 or 6 nmol of galanin, but not 1 nmol, induced significant bilateral increases in hindpaw withdrawal latencies to the hot-plate test, cold-plate test and the Randall Selitto tests in rats with left mononeuropathy. The results indicate that galanin may play important roles in transmission of presumed nociceptive information in the spinal cord of mononeuropathic rats.