PubMed · 267021
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1977. Fentanyl.. https://pubmed.ncbi.nlm.nih.gov/267021/
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To determine if intrathecal (i.t.) oxymetazoline (OXY) induces histological evidence of spinal neurotoxicity, male, Sprague-Dawley rats (300-450 g; implanted with an i.t. catheter) were treated with i.t. saline or 100 nmol OXY twice daily for 3 days, or 200 or 300 nmol OXY once daily for 3 days. Spantide (D-Arg1, D-Try7,9, Leu11-substance P; 0.067 nmol = 0.1 microgram, 0.167 nmol = 0.25 microgram or 0.334 nmol = 0.5 microgram) or capsaicin (0.164 mumol = 50 micrograms), given as a single i.t. injection, were used as positive controls. Animals were killed 12 h after the last injection of saline or OXY, and 72 h after spantide or capsaicin. Spinal cord sections (L1 and adjacent segments) were examined by light microscopy for changes in gross morphology, substance P-like immunoreactivity (SP-IR) and calcitonin gene related peptide-like immunoreactivity (CGRP-IR). All doses of i.t. OXY produced antinociception (tail-flick ED50 = 53.7 nmol, paw pressure withdrawal ED50 = 93.3 nmol). Rectal temperature decreased by 1.5-2.4 degrees C up to 12 h after 100 nmol of i.t. OXY. There were no signs of inflammation or necrosis, and no detectable loss or damage to either spinal afferents or motor neurons as judged by SP-IR and CGRP-IR structures in spinal cords of OXY-treated animals (all doses) as compared to i.t. saline controls. Spantide (0.1 microgram) had no antinociceptive or neurotoxic effect; 0.25 microgram induced irreversible loss of the TF reflex and transient hind limb paralysis; 0.5 microgram induced irreversible loss of TF and PP responses, permanent hind limb paralysis, bladder and bowel dysfunction. The spinal cords from these animals showed signs of extensive necrosis, cavitation, and haemorrhage in the ventral horn accompanied by a loss of CGRP-IR motor neurons. Capsaicin-treated rats exhibited a permanent loss of the TF but not the PP response and a marked reduction of SP-IR spinal afferents in the dorsal horn. It is concluded that i.t. OXY produces antinociception in the rat with no detectable spinal neurotoxicity as assessed by parameters which are sensitive to the neurotoxins, spantide and capsaicin.
This study examined whether two putative GABAB receptor antagonists, 4-amino-3-(5-methoxybenzo (b)furan-2-yl) butanoic acid (MBFG) and 4-amino-3-benzo(b)furan-2-yl butanoic acid (BFG), antagonized the antinociception produced by intrathecal (i.t) administration of the GABAB receptor agonist baclofen in the rat. In rats pretreated with 30 micrograms i.t. MBFG, the dose-effect relationship of D,L-baclofen was shifted approximately 2-fold and 4-fold to the right in the tail flick and hot plate tests, respectively. No further shift was obtained in the presence of 60 micrograms i.t. MBFG. I.t. injection of MBFG by itself did not alter either tail flick or hot plate latency. These data suggest that MBFG is a GABAB receptor antagonist in the spinal cord in vivo, although of marginal utility. Contrary to expectations, i.t. administration of 30-60 micrograms BFG alone increased tail flick and hot plate latencies; this increase was partially attenuated by coadministration of the GABAB receptor antagonist phaclofen. Pretreatment with 10 micrograms i.t. BFG, which was itself without effect on nociceptive threshold, antagonized the antinociceptive effects of 0.3 microgram i.t. L-baclofen, but interacted with higher and lower doses of baclofen in a complex manner. These results suggest that BFG acts as weak, partial agonist at GABAB receptors and that it may have additional, non-specific effects in the spinal cord of the rat. The pharmacological properties of BFG, therefore, resemble those of the GABAB receptor partial agonist/antagonist beta-phenyl-GABA, to which it bears a strong structural resemblance.(ABSTRACT TRUNCATED AT 250 WORDS)
The release of substance P (SP) from spinal dorsal horn slices is partially inhibited by micromolar concentrations of selective delta-opioid receptor agonists. In the present study, we have examined the effect of nanomolar concentrations of [D-Pen2,D-Pen5]enkephalin (DPDPE, delta-opioid receptor agonist) and low micromolar of concentrations morphine on K(+)-evoked SP release from rat trigeminal nucleus caudalis (TNC) slices. DPDPE and morphine inhibited SP release with an apparent maximal effect at 3 nM and at 3 microM, respectively. DPDPE and morphine produced U-shaped concentration-response curves that were completely autoinhibited at 100 nM DPDPE and 1 microM morphine. The inhibition of SP release produced by 3 nM DPDPE and 3 microM morphine was blocked by the opioid receptor antagonists naloxone (30 nM; non-selective) and ICI 174,864 (0.3 microM; delta-selective) but not by nor-binaltorphimine (3 nM n-BNI; kappa-selective), naloxonazine (1 nM; micro 1-selective) or beta-funaltrexamine (20 nM beta-FNA; mu-selective). These findings indicate that delta-opioid receptor-mediated inhibition of SP release from TNC can be achieved by nanomolar concentrations of selective delta-opioid receptor agonists. Activation of delta-opioid receptors by morphine might be involved in the residual analgesia observed after mu 1-opioid receptor blockade and in the analgesia produced by high doses of morphine.