A Novel Approach for the Control of Inflammatory Pain : Prostaglandin E2 Complexation by Randomly Methylated β-Cyclodextrins

2-Hydroxylpropyl-beta-cyclodextrin (HP-beta-CD) is an alternative to alpha-, beta- and gamma-cyclodextrin, with improved water solubility and may be more toxicologically benign. This paper reviews the toxicity of HP-beta-CD, using both literature information and novel data, and presents new information. In addition, it includes a brief review from studies of the metabolism and pharmacokinetics of HP-beta-CD in both humans and animals. This review concludes that HP-beta-CD is well tolerated in the animal species tested (rats, mice and dogs), particularly when dosed orally, and shows only limited toxicity. In short duration studies, there were slight biochemical changes whereas studies of a longer duration, up to three months, produced additional minor haematological changes but no histopathological changes. When dosed intravenously, histopathological changes were seen in the lungs, liver and kidney but all findings were reversible and no effect levels were achieved. The carcinogenicity studies showed an increase in tumours in rats in the pancreas and intestines which are both considered to be rat-specific. There were also non-carcinogenic changes noted in the urinary tract, but these changes were also reversible and did not impair renal function. There were no effects on embryo-foetal development in either rats or rabbits. HP-beta-CD has been shown to be well tolerated in humans, with the main adverse event being diarrhoea and there have been no adverse events on kidney function, documented to date.

Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL). To determine whether SFL is caused by spontaneous firing in nociceptive neurons, we studied the following groups of rats: (1) untreated; (2) spinal nerve axotomy (SNA), L5 SNA 1 week earlier; (3) mSNA (modified SNA), SNA plus loose ligation of the adjacent L4 spinal nerve with inflammation-inducing chromic gut; and (4) CFA (complete Freund's adjuvant), intradermal complete Freund's adjuvant-induced hindlimb inflammation 1 and 4 d earlier. In all groups, recordings of SFL and of spontaneous activity (SA) in ipsilateral dorsal root ganglion (DRG) neurons (intracellularly) were made. Evoked pain behaviors were measured in nerve injury (SNA/mSNA) groups. Percentages of nociceptive-type C-fiber neurons (C-nociceptors) with SA increased in intact L4 but not axotomized L5 DRGs in SNA and mSNA (to 35%), and in L4/L5 DRGs 1-4 d after CFA (to 38-25%). SFL occurred in mSNA but not SNA rats. It was not correlated with mechanical allodynia, extent of L4 fiber damage [ATF3 (activation transcription factor 3) immunostaining], or percentage of L4 C-nociceptors with SA. However, L4 C-nociceptors with SA fired faster after mSNA (1.8 Hz) than SNA (0.02 Hz); estimated L4 total firing rates were approximately 5.0 and approximately 0.6 kHz, respectively. Similarly, after CFA, faster L4 C-nociceptor SA after 1 d was associated with SFL, whereas slower SA after 4 d was not. Thus, inflammation causes L4 C-nociceptor SA and SFL. Overall, SFL was related to SA rate in intact C-nociceptors. Both L5 degeneration and chromic gut cause inflammation. Therefore, both SA and SFL/spontaneous pain after nerve injury (mSNA) may result from cumulative neuroinflammation.