Upregulated 5-HT1A Receptors Regulate Lower Urinary Tract Function in Rats after Complete Spinal Cord Injury.

Spinal cord injury (SCI) above the lumbosacral level often leads to dysfunction of the lower urinary tract (LUT) including detrusor hyper-reflexia, wherein bladder compliance is low, baseline pressures are increased, and filling is accompanied by numerous non-voiding contractions (NVCs) referred to as neurogenic detrusor overactivity. Here, we investigate the expression levels of the serotonin 1A (5-HT1A) receptor in segments both rostral and caudal to the injured site, as well as the effects on micturition of blocking 5-HT1A receptor using pharmacological interventions in spinally intact rats or T8 complete SCI rats. The activities of detrusor and external urethral sphincter (EUS) were assessed with the rats in a conscious condition. Adult female rats were divided into two groups: (1) sham control (T8 laminectomy only) and (2) T8 complete spinal cord transection. The observation period was 2 months after the original SCI. In Western blot analyses, we identified significant upregulation of the 5-HT1A receptor in the T10-L2 and L6/S1 segments after chronic complete SCI. In pharmacological studies, a dose-response study of the 5-HT1A receptor antagonist, WAY100635, indicated alterations in detrusor and EUS activities in spinally intact rats. Interestingly, blocking the 5-HT1A receptor alone resulted in inhibitory effects on NVCs with a reduced number and decreased amplitude, but in an increased interval between NVCs in SCI rats. In addition, the duration of EUS bursting was also significantly increased by WAY100635. These inhibitory effects of WAY100635 on NVCs were diminished by subsequent application of a beta-adrenergic blocker (propranolol). The reduction of NVCs observed by WAY100635 may be the result of blocking the constitutive activities of the 5-HT1A receptor but activating the beta-adrenergic sympathetic pathway, which in turn relaxes bladder activity. Together, the neuroplasticity of the 5-HT1A receptor can be a potential therapeutic target for treatment of bladder dysfunction after SCI.

Ontogeny of effective mechanical advantage in eastern cottontail rabbits (Sylvilagus floridanus).

Juvenile animals must survive in the same environment as adults despite smaller sizes, immature musculoskeletal tissues, general ecological naïveté and other limits of performance. Developmental changes in muscle leverage could constitute one mechanism to promote increased performance in juveniles despite ontogenetic limitations. We tested this hypothesis using a holistic dataset on growth and locomotor development in wild eastern cottontail rabbits (Sylvilagus floridanus) to examine ontogenetic changes in hindlimb muscle effective mechanical advantage (EMA). EMA is a dimensionless index of muscle leverage, equal to the quotient of average muscle lever length and the load arm length of the ground reaction force (GRF), effectively representing the magnitude of output force arising from a given muscle force. We found that EMA at the hip and ankle joints, as well as overall hindlimb EMA, significantly declined across ontogeny in S. floridanus, whereas EMA at the knee joint remained unchanged. Ontogenetic decreases in EMA were due to isometric scaling of muscle lever arm lengths alongside positive ontogenetic allometry of GRF load arm lengths - which in turn was primarily related to positive allometry of hindlimb segment lengths. Greater EMA limits the estimated volume of hindlimb extensor muscle that has to be activated in young rabbits, likely mitigating the energetic cost of locomotion and saving metabolic resources for other physiological functions, such as growth and tissue differentiation. An additional examination of limb growth allometry across a diverse sample of mammalian taxa suggests that ontogenetic decreases in limb joint EMA may be a common mammalian trend.