Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.

OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.

Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

OBJECTIVE: To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). METHODS: Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. RESULTS: A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. CONCLUSION: The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.

Macrophage migration inhibitory factor in the bovine corpus luteum: characterization of steady-state messenger ribonucleic acid and immunohistochemical localization.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine produced by T cells and macrophages. A number of tissues also produce MIF during states of active differentiation and/or proliferation. The purpose of this study was to determine whether MIF is present in the corpus luteum (CL). The steady-state mRNA for MIF was examined in CL by Northern analysis on Day 5, Days 9-12, and Day 18 of the estrous cycle and at 0.5, 1, 4, 12, 24, and 36 h after a luteolytic injection of prostaglandin F(2alpha) (PGF(2alpha)) (n = 4 CL per time point). The greatest amount of MIF mRNA was observed in Day 5 CL compared with midcycle and Day 18 CL. Messenger RNA for MIF in CL collected 0.5 h post-PGF(2alpha) was greater than in midcycle and all other regressing CL. Immunohistochemical analysis (n = 4) revealed that MIF was present in the bovine CL throughout the estrous cycle and appeared to be localized to large luteal cells. It was concluded that MIF is produced within the bovine CL, mRNA expression is maximal in the early CL, and the protein is primarily localized to large luteal cells. The functional significance of MIF remains to be determined.

Estrogen withdrawal induces macrophage invasion in the rabbit corpus luteum.

Macrophages within the corpus luteum are associated with spontaneous luteal regression in a number of species. However, an understanding of the consequences of macrophage recruitment on the functional capacity and responsiveness of the luteal tissue has remained elusive. Here we investigate the temporal appearance of macrophages and their potential impact in corpora lutea of rabbits, in which a rapid fall in progesterone synthesis and premature regression of the corpus luteum are initiated by withdrawal of the luteotropic hormone estradiol-17beta. Removal of estradiol implants, placed subcutaneously, induced a significant increase in the average number of macrophages per high-power field (hpf) in corpora lutea (p < 0.05) within 72 h. Replacement of the estradiol implants 48 h after their removal resulted in a marginal rebound of plasma progesterone and a variable number of luteal macrophages (range: 6-160 macrophages/hpf) among the 11 rabbits. A third experiment revealed that the relative numbers of macrophages within the corpora lutea have no apparent relationship to rates of progesterone synthesis in vitro: progesterone production (ng/mg tissue) did not differ (p > 0.05) between corpora lutea of estradiol-maintained rabbits and those of estradiol-replaced rabbits despite obvious differences in numbers of luteal macrophages (2 +/- 1 vs. 42 +/- 10 macrophages/hpf, respectively; p < 0.05). We conclude that the entry/recruitment of macrophages into the rabbit corpus luteum is sensitive to the luteotropic hormone estradiol-17beta and that the presence of macrophages does not preclude the continuation of progesterone production in surviving luteal tissue revitalized after estradiol removal/replacement.