# Phenylephrine per se or Combined with Pregabalin Ameliorates Mononeuropathic Pain in Rats

## TL;DR

This study finds that combining phenylephrine with pregabalin may help reduce nerve pain in rats without major side effects.

## Contribution

The novel finding is that combining phenylephrine and pregabalin, but not either alone, effectively reduces neuropathic pain in rats.

## Key findings

- Intrathecal phenylephrine reduces tactile allodynia in rats with nerve injury.
- Combining phenylephrine and pregabalin acutely and chronically alleviates allodynia without cardiovascular side effects.
- Phenylephrine induces noradrenaline release and smooth muscle contraction in a receptor-dependent manner.

## Abstract

Background/Objectives: Neuropathic pain (NP) affects approximately 6.9–10% of the population and is inadequately managed by the current therapies, as reflected by a high number needed to treat (NNT). These data highlight the socio-economic burden of NP on healthcare. Thus, the repurposing of existing medications and new drug combinations to enhance therapeutic efficacy are required. Methods/Results: Here, we show that intrathecal phenylephrine (PE) in a dose of 3, 10, or 30 nmol/rat acutely alleviates tactile allodynia in rats with mononeuropathic pain evoked by partial sciatic nerve ligation. Prazosin and idazoxan, which are considered as selective α1- and α2-adrenoreceptor antagonists, respectively, reversed the antiallodynic effects of PE. In ex vivo experiments, PE induced a significant cytosolic [3H]-noradrenaline release from mouse spinal tissue. In addition, in the mouse vas deferens, PE produced smooth muscle contraction in prazosin and idazoxan sensitive manner. As a novelty, in another set of experiments, oral PE (5 mg/kg) and pregabalin (PGB, 25 mg/kg) combination, but not the individual drug treatments, acutely alleviated allodynia in rats with mononeuropathy. In addition, the antiallodynic action of the combination was further enhanced upon chronic treatment. Under isoflurane anesthesia, this combination was devoid of cardiovascular side effects attributed to systolic and diastolic blood pressure, mean arterial pressure, or heart rate. PGB induced motor dysfunction was not altered upon the combination with PE. Conclusions: These data suggest that PE in combination with PGB shows promise in preclinical settings; however, the necessity for further studies is paramount to detail the pharmacokinetic interactions involved.